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11
Macronutrients and
Healthful Diets
SUMMARY
Acceptable Macronutrient Distribution Ranges (AMDRs) for indi-
viduals have been set for carbohydrate, fat, n-6 and n-3 poly-
unsaturated fatty acids, and protein based on evidence from
interventional trials, with support of epidemiological evidence that
suggests a role in the prevention or increased risk of chronic dis-
eases, and based on ensuring sufficient intakes of essential nutrients.
The AMDR for fat and carbohydrate is estimated to be 20 to 35
and 45 to 65 percent of energy for adults, respectively. These
AMDRs are estimated based on evidence indicating a risk for coro-
nary heart disease (CHD) at low intakes of fat and high intakes of
carbohydrate and on evidence for increased risk for obesity and
its complications (including CHD) at high intakes of fat. Because
the evidence is less clear on whether low or high fat intakes during
childhood can lead to increased risk of chronic diseases later in
life, the estimated AMDRs for fat for children are primarily based
on a transition from the high fat intakes that occur during infancy
to the lower adult AMDR. The AMDR for fat is 30 to 40 percent of
energy for children 1 to 3 years of age and 25 to 35 percent
of energy for children 4 to 18 years of age. The AMDR for carbo-
hydrate for children is the same as that for adultsâ45 to 65 percent
of energy. The AMDR for protein is 10 to 35 percent of energy for
adults and 5 to 20 percent and 10 to 30 percent for children 1
to 3 years of age and 4 to 18 years of age, respectively.
769

770 DIETARY REFERENCE INTAKES
Based on usual median intakes of energy, it is estimated that a
lower boundary level of 5 percent of energy will meet the Adequate
Intake (AI) for linoleic acid (Chapter 8). An upper boundary for
linoleic acid is set at 10 percent of energy for three reasons:
(1) individual dietary intakes in the North American population
rarely exceed 10 percent of energy, (2) epidemiological evidence
for the safety of intakes greater than 10 percent of energy are
generally lacking, and (3) high intakes of linoleic acid create a
pro-oxidant state that may predispose to several chronic diseases,
such as CHD and cancer. Therefore, an AMDR of 5 to 10 percent
of energy is estimated for n-6 polyunsaturated fatty acids (linoleic
acid).
An AMDR for Î±-linolenic acid is estimated to be 0.6 to 1.2 percent
of energy. The lower boundary of the range meets the AI for
Î±-linolenic acid (Chapter 8). The upper boundary corresponds to
the highest Î±-linolenic acid intakes from foods consumed by indi-
viduals in the United States and Canada. A growing body of litera-
ture suggests that higher intakes of Î±-linolenic acid, eicosapentaenoic
acid (EPA), and docosahexaenoic acid (DHA) may afford some
degree of protection against CHD. Because the physiological
potency of EPA and DHA is much greater than that for Î±-linolenic
acid, it is not possible to estimate one AMDR for all n-3 fatty acids.
Approximately 10 percent of the AMDR can be consumed as EPA
and/or DHA.
No more than 25 percent of energy should be consumed as added
sugars. This maximal intake level is based on ensuring sufficient
intakes of certain essential micronutrients that are not present in
foods and beverages that contain added sugars. A daily intake of
added sugars that individuals should aim for to achieve a healthy
diet was not set.
A Tolerable Upper Intake Level (UL) was not set for saturated
fatty acids, trans fatty acids, or cholesterol (see Chapters 8 and 9).
This chapter provides some guidance in ways of minimizing the
intakes of these three nutrients while consuming a nutritionally
adequate diet.
INTRODUCTION
Unlike micronutrients, macronutrients (fat, carbohydrate, and pro-
tein) are sources of body fuel that can be used somewhat interchangeably.
Thus, for a certain level of energy intake, increasing the proportion of one
macronutrient necessitates decreasing the proportion of one or both of
the other macronutrients. The majority of energy is consumed as carbo-

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M ACRONUTRIENTS AND HEALTHFUL DIETS
hydrate (approximately 35 to 70 percent, primarily as starch and sugars),
and fat (approximately 20 to 45 percent), while the contribution of protein
to energy intake is smaller and less varied (10 to 23 percent) (Appendix
Tables E-3, E-6, and E-17). Therefore, a high fat diet (high percent of
energy from fat) is usually low in carbohydrate and vice versa. In addition
to these macronutrients, alcohol can provide on average up to 3 percent
of energy of the adult diet (Appendix Table E-18).
A small amount of carbohydrate and as n-6 (linoleic acid) and n-3
(Î±-linolenic acid) polyunsaturated fatty acids and a number of amino acids
that are essential for metabolic and physiological processes, are needed by
the brain. The amounts needed, however, each constitute only a small
percentage of total energy requirements. Food sources vary in their con-
tent of particular macro- and micronutrients. While some nutrients are
present in both animal- and plant-derived foods, others are only present
or are more abundant in either animal or plant foods. For example,
animal-derived foods contain significant amounts of protein, saturated fatty
acids, long-chain n-3 polyunsaturated fatty acids, and the micronutrients
iron, zinc, and vitamin B12, while plant-derived foods provide greater
amounts of carbohydrate, Dietary Fiber, linoleic and Î±-linolenic acids, and
micronutrients such as vitamin C and the B vitamins. It may be difficult to
achieve sufficient intakes of certain micronutrients when consuming foods
that contain very low amounts of a particular macronutrient. Alternatively,
if intake of certain macronutrients from nutrient-poor sources is too high,
it may also be difficult to consume sufficient micronutrients and still
remain in energy balance. Therefore, a diet containing a variety of foods is
considered the best approach to ensure sufficient intakes of all nutrients.
This concept is not new and has been part of nutrition education pro-
grams since the early 1900s. For example, the first U.S. food guide was
developed by the U.S. Department of Agriculture in 1916 and suggested
consumption of a combination of five different food groups (Guthrie and
Derby, 1998). This food guide has evolved to become known as the Food
Guide Pyramid (USDA, 1996). Similarly, Canada has developed Canadaâs
Food Guide to Healthy Eating (Health Canada, 1997).
A growing body of evidence indicates that an imbalance in macro-
nutrients (e.g., low or high percent of energy), particularly with certain
fatty acids and relative amounts of fat and carbohydrate, can increase risk
of several chronic diseases. Much of this evidence is based on epidemio-
logical studies of clinical endpoints such as coronary heart disease (CHD),
diabetes, cancer, and obesity. However, these studies demonstrate associa-
tions; they do not necessarily infer causality, such as would be derived
from controlled clinical trials. Robust clinical trials with specified clinical
endpoints are generally lacking for macronutrients. Of importance, fac-
tors other than diet contribute to chronic disease, and multifactorial cau-

772 DIETARY REFERENCE INTAKES
sality of chronic disease can confound the long-term adverse effects of a
given macronutrient distribution. It is not possible to determine a defined
level of intake at which chronic disease may be prevented or may develop.
For example, high fat diets may predispose to obesity, but at what percent
of energy intake does this occur? The answer depends on whether energy
intake exceeds energy expenditure or is balanced with physical activity.
This chapter reviews the scientific evidence on the role of macro-
nutrients in the development of chronic disease. In addition, the nutrient
limitations that can occur with the consumption of too little or too much
of a particular macronutrient are discussed. In consideration of the inter-
relatedness of macronutrients, their role in chronic disease, and their
association with other essential nutrients in the diet, Acceptable Macro-
nutrient Distribution Ranges (AMDRs) are estimated and represented as
percent of energy intake. These ranges represent (1) intakes that are asso-
ciated with reduced risk of chronic disease, (2) intakes at which essential
dietary nutrients can be consumed at sufficient levels, and (3) intakes
based on adequate energy intake and physical activity to maintain energy
balance. When intakes of macronutrients fall above or below the AMDR,
the risk for development of chronic disease (e.g., diabetes, CHD, cancer)
appears to increase.
DIETARY FAT AND CARBOHYDRATE
There are a number of adverse health effects that may result from
consuming a diet that is too low or high in fat or carbohydrate (starch and
sugars). Furthermore, chronic consumption of a low fat, high carbohydrate
or high fat, low carbohydrate diet may result in the inadequate intake of
certain essential nutrients.
Low Fat, High Carbohydrate Diets of Adults
The chronic diseases of greatest concern with respect to relative intakes
of macronutrients are CHD, diabetes, and cancer. In this section, the rela-
tionship between total fat and total carbohydrate intakes are considered.
Comparisons are made in terms of percentage of total energy intake. For
example, a low fat diet signifies a lower percentage of fat relative to total
energy. It does not imply that total energy intake is reduced because of
consumption of a low amount of fat. The distinction between hypocaloric
diets and isocaloric diets is important, particularly with respect to impact on
body weight. Low and high fat diets can still be isocaloric. The failure to
identify this distinction has led to considerable confusion in terms of the
role of dietary fat in chronic disease.

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M ACRONUTRIENTS AND HEALTHFUL DIETS
energy consumed as fat (greater than 4 percent) resulted in small losses in
body weight. The only study that provided isocaloric diets showed no dif-
ferences in weight gain or loss, despite a wide range in the percent of
energy from fat (Leibel et al., 1992). Four meta-analyses of long-term
intervention studies associating a low fat diet with body weight concluded
that lower fat diets lead to modest weight loss or prevention of weight gain
(Astrup et al., 2000; Bray and Popkin, 1998; Hill et al., 2000; Yu-Poth et al.,
1999). These studies thus suggest that low fat diets (low percentage of fat)
tend to be slightly hypocaloric compared to higher fat diets when com-
pared in outpatient intervention trials.
The finding that higher fat diets are moderately hypercaloric when
compared with reduced fat intakes under ad libitum conditions provides a
rationale for setting an upper boundary for percentage of fat intake in a
population that already has a high prevalence of overweight and obesity.
However, a second issue must also be addressed: whether the distribution
of fat and carbohydrate modifies the metabolic consequences of over-
weight and obesity. Two of the more important consequences of obesity
are dyslipidemic changes in serum lipoproteins (which predispose to CHD)
and changes in glucose and insulin metabolism that accentuate an under-
lying insulin resistance (which may predispose to both CHD and diabetes).
These consequences are discussed in the following sections.
Risk of CHD
Low fat, high carbohydrate diets, compared to higher fat intakes, can
induce a lipoprotein pattern called the atherogenic lipoprotein pheno-
type (Krauss, 2001) or atherogenic dyslipidemia (National Cholesterol
Education Program, 2001). In populations where people are routinely
physically active and lean, the atherogenic lipoprotein phenotype is mini-
mally expressed. In sedentary populations that tend to be overweight or
obese, very low fat, high carbohydrate diets clearly promote the develop-
ment of this phenotype. Whether this phenotype promotes development
of coronary atherosclerosis when it is specifically induced by low fat diets is
uncertain, but it is a pattern that is associated with increased risk for CHD
when expressed in the general American population. The atherogenic
lipoprotein phenotype is characterized by higher triacylglycerol and
decreased high density lipoprotein (HDL) cholesterol concentrations and
small low density lipoprotein (LDL) particles. A predominance of small
LDL particles is associated with a greater risk of CHD (Austin et al., 1990),
but it is not known if this association is independent of increased
triacylglycerol and decreased HDL cholesterol concentrations.
Table 11-2 and Figures 11-1 and 11-2 show that with decreasing fat and
increasing carbohydrate intake, plasma triacylglycerol concentrations

784 DIETARY REFERENCE INTAKES
total:HDL cholesterol ratios) and CHD risk provides one rationale for
establishing a lower boundary for the Acceptable Macronutrient Distribu-
tion Range (AMDR) for high-risk populations.
Risk of Hyperinsulinemia, Glucose Intolerance, and Type 2 Diabetes
Other potential abnormalities accompanying changes in distribution
of fat and carbohydrate intakes include increased postprandial responses
in plasma glucose and insulin concentrations. These abnormalities are
more likely to occur with low fat, high carbohydrate diets. They potentially
could be related to the development of both type 2 diabetes and CHD. In
particular, repeated daily elevations in postprandial glucose and insulin
concentrations could âexhaustâ pancreatic Î²-cells of insulin supply, which
could hasten the onset of type 2 diabetes. Some investigators have further
suggested these repeated elevations could worsen baseline insulin sensitivity,
which could cause susceptible persons to be at increased risk for type 2
diabetes. This form of diabetes, defined by an elevation of fasting serum
glucose concentration, is characterized by two defects in glucose metabolism:
insulin resistance, a defect in insulin-mediated uptake of glucose by cells,
particularly skeletal muscle cells, and a decline in insulin secretory capacity
by pancreatic Î²-cells (Turner and Clapham, 1998). Insulin resistance typi-
cally precedes the development of type 2 diabetes by many years. It is
known to be the result of obesity, physical inactivity, and genetic factors
(Turner and Clapham, 1998). Before the onset of diabetic hyperglycemia,
the pancreatic Î²-cells are able to respond to insulin resistance with an
increased insulin secretion, enough to maintain normoglycemia. However,
in some persons who are insulin resistant, insulin secretory capacity declines
and hyperglycemia ensues (Reaven, 1988, 1995).
The mechanisms for the decline in insulin secretion are not well
understood, but one theory is that continuous overstimulation of insulin
secretion by the presence of insulin resistance leads to âinsulin exhaustionâ
and hence to decreased insulin secretory capacity (Turner and Clapham,
1998). Whether insulin exhaustion is secondary to a metabolic dysfunction
of cellular production of insulin or to a loss of Î²-cells is uncertain. The
accumulation of pancreatic islet-cell amyloidosis may be one mechanism
for loss of insulin-secretory capacity (HÃ¶ppener et al., 2000).
High carbohydrate diets frequently causes greater insulin and plasma
glucose responses than do low carbohydrate diets (Chen et al., 1988;
Coulston et al., 1987). These excessive responses theoretically could pre-
dispose individuals to the development of type 2 diabetes because of pro-
longed overstimulation of insulin secretion (Grill and BjÃ¶rklund, 2001).
The reasoning is similar to that for insulin resistance, namely, excessive
stimulation of insulin secretion over a period of many years could result in

785
M ACRONUTRIENTS AND HEALTHFUL DIETS
insulin exhaustion, and hence to hyperglycemia (Turner and Clapham,
1998). This mechanism, although plausible, remains hypothetical. None-
theless, in the mind of some investigators, it deserves serious consideration.
Other consequences of hyperglycemic responses to high carbohydrate
diets might be considered. For example, higher postprandial glucose
responses might lead to other changes such as âdesensitizationâ of Î²-cells
for insulin secretion and production of glycated products or advanced
glycation end-products, which could either promote atherogenesis or the
âagingâ process (Lopes-Virella and Virella, 1996). Again, these are hypo-
thetical consequences that need further examination.
Epidemiological Evidence. A number of noninterventional, epidemio-
logical studies have shown no relationship between carbohydrate intake
and risk of diabetes (Colditz et al., 1992; Lundgren et al., 1989; Marshall et
al., 1991; Meyer et al., 2000; SalmerÃ³n et al., 1997), whereas other studies
have shown a positive association (Bennett et al., 1984; Feskens et al.,
1991a).
Interventional Evidence. Interventional studies in healthy individuals on
the influence of high carbohydrate diets on biomarker precursors for type
2 diabetes are lacking and the available data are mixed (Table 11-4) (Beck-
Nielsen et al., 1980; Chen et al., 1988; Dunnigan et al., 1970; Fukagawa et
al., 1990; Rath et al., 1974; Reiser et al., 1979). Factors such as carbo-
hydrate quality, body weight, exercise, and genetics make the interpretation
of such findings difficult. Nonetheless, in overweight and sedentary groups
(which carry a heavy burden of insulin resistance and are common in
North America), the accentuation of postprandial glucose and insulin
concentrations that accompany high carbohydrate diets are factors to con-
sider when setting an upper boundary for AMDRs for dietary carbohydrate
(and a lower boundary for dietary fat).
Risk of Nutrient Inadequacy or Excess
Diets Low in Fats. For usual diets that are low in total fat, the intake of
essential fatty acids, such as n-6 polyunsaturated fatty acids, will be low
(Appendix K). In general, with increasing intakes of carbohydrate and
decreasing intakes of fat, the intake of n-6 polyunsaturated fatty acids
decreases. Furthermore, low intakes of fat are associated with low intakes
of zinc and certain B vitamins.
The digestion and absorption of fat-soluble vitamins and provitamin A
carotenoids are associated with fat absorption. Jayarajan and coworkers
(1980) reported that the addition of 5 or 10 g of fat to a low fat (5 g) diet

788 DIETARY REFERENCE INTAKES
significantly improved serum vitamin A concentrations. However, the addi-
tion of 10 g compared to 5 g did not provide any further benefit. The level
of dietary fat has also been shown to improve vitamin K2 bioavailability
(Uematsu et al., 1996). Doseâresponse data are limited on the amount of
dietary fat needed to achieve the optimal absorption of fat-soluble vitamins,
but it appears that the level is quite low.
Diets High in Fiber. Most diets that are high in fiber are also high in
carbohydrate . High fiber diets have the potential for reduced energy
density, reduced energy intake, and poor growth. However, poor growth is
unlikely in the United States where most children consume adequate
energy and fiber intake is relatively low (Williams and Bollella, 1995). Miles
(1992) tested the effects of daily ingestion of 64 g or 34 g of Dietary Fiber for
10 weeks in healthy adult males. The ingestion of 64 g/d of Dietary Fiber
resulted in a reduction in protein utilization from 89.4 to 83.7 percent and
in fat utilization from 95.5 to 92.5 percent. Total energy utilization
decreased from 94.3 to 91.4 percent. Because most individuals consuming
high amounts of fiber would also be consuming high amounts of energy,
the slight depression in energy utilization is not significant (Miles, 1992).
In other studies, ingestion of high amounts of fruit, vegetable, and cereal
fiber (48.3 to 85.6 g/d) also resulted in decreases in apparent digestibilities
of energy, crude protein, and fat (GÃ¶ranzon et al., 1983; Wisker et al.,
1988). Again, however, the Dietary Fiber intakes were very high, and because
the recommendation for Total Fiber intake is related to energy intake, the
high fiber consumers would also be high energy consumers.
Diets High in Added Sugars. Increased consumption of added sugars
can result in decreased intakes of certain micronutrients (Table 11-5).
This can occur because of the abundance of added sugars in energy-dense,
nutrient-poor foods, whereas naturally occurring sugars are primarily
found in fruits, milk, and dairy products that also contain essential micro-
nutrients. Because some micronutrients (e.g., vitamin B6, vitamin C, and
folate), dietary fiber, and phytochemicals were not examined, the association
between these nutrients and added sugars intakes is not known. Bowman
(1999) used data from Continuing Survey of Food Intakes of Individuals
(CSFII) (1994â1996) to assess the relationship between added sugars and
intakes of essential nutrients in Americansâ diets. The sample (n = 14,704)
was divided into three groups based on the percentage of energy consumed
from added sugars: (1) less than 10 percent of total energy (n = 5,058),
(2) 10 to 18 percent of total energy (n = 4,488), and (3) greater than
18 percent of total energy (n = 5,158). Group 3, with a mean of 26.7 percent
of energy from added sugars, had the lowest absolute mean intakes of all

789
M ACRONUTRIENTS AND HEALTHFUL DIETS
the micronutrients, especially vitamin A, vitamin C, vitamin B12, folate,
calcium, phosphorus, magnesium, and iron. Compared with Groups 1 and
2, a decreased percentage of people in Group 3 met their Recommended
Dietary Allowance (RDA) for many micronutrients. The individuals in
Group 3 did not meet the 1989 RDA for vitamin E, vitamin B6, calcium,
magnesium, and zinc. In addition, the high sugar consumers (Group 3)
had lower intakes of grains, fruits, vegetables, meat, poultry, and fish com-
pared with Groups 1 and 2. At the same time, Group 3 consumed more
soft drinks, fruit drinks, punches, ades, cakes, cookies, grain-based pastries,
milk desserts, and candies. Similar trends were also reported by Bolton-
Smith and Woodward (1995) and Forshee and Storey (2001), but were not
observed by Lewis and coworkers (1992). Emmett and Heaton (1995)
reported an overall deterioration in the quality of the diet in heavy users
of added sugars.
Using 1990â1991 cross-sectional data, Guthrie (1996) found that
women whose diets met their RDA for calcium consumed significantly
more milk products, fruit, and grains, and less regular soft drinks than
women who did not meet their calcium recommendations. Others have
shown that intakes of soft drinks are negatively related to intakes of milk
(Guenther, 1986; Harnack et al., 1999; Skinner et al., 1999).
To further look at the association between added sugars and certain
micronutrient intakes, the median intakes of various micronutrients at
every 5th percentile of added sugars intake was determined using data
from the Third National Health and Nutrition Examination Survey
(NHANES III) (Appendix J). In addition, the prevalence of subpopulations
not meeting the Estimated Average Requirement (EAR) or exceeding the
Adequate Intake (AI) for these micronutrients was determined. Because
not all micronutrients and other nutrients, such as fiber, were evaluated, it
is not known what the association is between added sugars and these
nutrients. While the trends are not consistent for all age groups, reduced
intakes of calcium, vitamin A, iron, and zinc were observed with increasing
intakes of added sugars, particularly at intake levels exceeding 25 percent
of energy. Although this approach has limitations, it gives guidance for the
planning of healthy diets.
Diets High in Total Sugars. In one large dietary survey, linear reductions
were observed for certain micronutrients when total sugars intakes increased
(Bolton-Smith and Woodward, 1995), whereas no consistent reductions
were observed in another survey (Gibney et al., 1995) (Table 11-6). Bolton-
Smith (1996) reviewed the literature on the relation of sugars intake to
micronutrient adequacy and concluded that, provided consumption of
sugars is not excessive (defined as less than 20 percent of total energy
intake), no health risks are likely to ensue due to micronutrient inadequacies.

794 DIETARY REFERENCE INTAKES
gain and high fat intake. One statistically well-designed study that included
direct measurements of body fat and considered potentially confounding
factors such as exercise concluded that total dietary fat was positively cor-
related with fat mass (adjusted for fat-free mass, r = 0.22, p < 0.0001) in
adults (Larson et al., 1996). Most multiple regression studies found that
about 3 percent of the total variance in body fatness was explained by diet,
though some studies placed the estimate at 7 to 8 percent (Westerterp et
al., 1996). Longitudinal studies generally supported dietary fat as a predic-
tive factor in the development of obesity (Lissner and Heitmann, 1995).
However, bias in subject participation, retention, and underreporting of
intake may limit the power of these epidemiological studies to assess the
relationship between dietary fat and obesity or weight gain (Lissner et al.,
2000).
Another line of evidence often cited to indicate that dietary fat is not
an important contributor to obesity is that although there has been a
reduction in the percent of energy from fat consumed in the United States,
there has been an increase in energy intake and a marked gain in average
weight (Willett, 1998). Survey data showed an increase in total energy
intake over this period (McDowell et al., 1994), so that despite the decline
in percent of energy from fat, the total intake of fat (g/d) remained stable.
Another study that used food supply data showed that fat intake may
indeed be rising in the United States (Harnack et al., 2000).
Mechanisms for Obesity and Interventional Evidence. Several mechanisms
have been proposed whereby high fat intakes could lead to excess body
accumulation of fat. Foods containing high amounts of fat tend to be
energy dense, and the fat is a major contributor to the excess energy con-
sumed by persons who are overweight or obese (Prentice, 2001). The
energy density of a food can be defined as the amount of metabolizable
energy per unit weight or volume (Yao and Roberts, 2001); water and fat
are the main determinants of dietary energy density. Energy density is an
issue of interest to the extent that it influences energy intake and thus
plays a role in energy regulation, weight maintenance, and the subsequent
development of obesity.
Three theoretical mechanisms have been identified by which dietary
energy density may affect total energy intake and hence energy regulation
(Yao and Roberts, 2001). Some studies suggest that, at least in the short-
term, individuals tend to eat in order to maintain a constant volume of
food intake because stomach distension triggers vagal signals of fullness
(Duncan et al., 1983; Lissner et al., 1987; Seagle et al., 1997; Stubbs et al.,
1995a). Thus, consumption of high energy-dense foods could lead to
excess energy intake due to the high energy density to small food volume
ratio.

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M ACRONUTRIENTS AND HEALTHFUL DIETS
A second proposed mechanism is that high energy-dense foods are
often more palatable than low energy-dense foods (Drewnowski, 1999;
Drewnowski and Greenwood, 1983). A survey of American adults reported
that taste is the primary influence for food choice (Glanz et al., 1998). In
single-meal studies, high palatability was also associated with increased food
consumption (Bobroff and Kissileff, 1986; Price and Grinker, 1973;
Yeomans et al., 1997). These results suggest that high energy-dense foods
may be overeaten because of effects related to their high palatability.
The third mechanism is that energy-dense foods reduce the rate of
gastric emptying (Calbet and MacLean, 1997; Wisen et al., 1993). This
reduction, however, does not occur proportionally to the increase in
energy density. Although energy-dense foods reduce the rate at which food
leaves the stomach, they actually increase the rate at which energy leaves
the stomach. Thus, because energy-containing nutrients are digested more
quickly, nutrient levels in the blood fall quicker and hunger returns
(Friedman, 1995). While a subjective measure, highly palatable meals have
also been shown to produce an increased glycemic response compared
with less palatable meals that contain the same food items that are com-
bined in different ways (Sawaya et al., 2001). This suggests a generalized
link among palatability, gastric emptying, and glycemic response in the
underlying mechanisms determining the effects of energy density on
energy regulation. Further research on this potential link is needed.
Researchers have used instruments such as visual analogue scales to
measure differences in appetite sensations (e.g., hunger and satiety)
between treatments in order to examine the effects of altering nutrients
that play a major role in energy density, such as dietary fat, on energy
regulation (Flint et al., 2000). A number of studies have been conducted
in which preloads of differing energy density were given and hunger and
satiety were measured either at the subsequent meal or for the remainder
of the day. In the studies that administered preloads that had constant
volume but different energy content (energy density was altered by chang-
ing dietary fat content), there was no consistent difference in subsequent
satiety or hunger between the various test meals (Durrant and Royston,
1979; Green et al., 1994; Hill et al., 1987; Himaya et al., 1997; Hulshof et
al., 1993; Louis-Sylvestre et al., 1994; Porrini et al., 1995; Rolls et al., 1994).
However, in those studies using isoenergetic preloads that differed in
volume (energy density was altered by changing dietary fat content), there
was consistently increased satiety and reduced hunger after consumption
of the low energy-dense preload meals (i.e., those with higher volume)
(Blundell et al., 1993; Holt et al., 1995; van Amelsvoort et al., 1989, 1990).
It has been reported, however, that diets low in fat and high in carbo-
hydrate may lead to more rapid return of hunger and increased snacking
between meals (Ludwig et al., 1999a).

796 DIETARY REFERENCE INTAKES
These data suggest that in the short-term, low energy-dense foods
appear to increase satiety and decrease hunger compared to high energy-
dense foods. Because individuals were blinded to the dietary content of
the treatment diets, the results from these studies demonstrate the short-
term effects of energy density after controlling for cognitive influences on
food intake.
It is important that cognitive factors are taken into account during the
interpretation of results of preload studies. When individuals were aware
of dietary changes, they generally (Ogden and Wardle, 1990; Shide and
Rolls, 1995; Wooley, 1972), but not always (Mattes, 1990; Rolls et al., 1989),
compensated for changes in energy density and thus minimized changes
in energy intake.
In well-controlled, short-term intervention studies lasting several days
or more, high fat diets were consistently associated with higher spontaneous
energy intake (Lawton et al., 1993; Proserpi et al., 1997; Thomas et al.,
1992). From short- and longer-term studies, volunteers consistently con-
sumed less dietary energy on low fat, low energy dense diets compared to
high energy-dense diets (Glueck et al., 1982; Lissner et al., 1987; Poppitt
and Swann, 1998; Poppitt et al., 1998; Stubbs et al., 1995b; Thomas et al.,
1992; Tremblay et al., 1989, 1991). The extent to which energy intake was
reduced on low energy-dense diets was similar for short- and long-term
studies.
An alternative way to study the effects of energy density on energy
intake in short-term studies has been to compare energy intake between
diets of similar energy density that differ in dietary fat content. Using this
approach, when fat content was covertly varied between 20 and 60 percent
of energy, there was no significant difference in energy intake between
groups (Saltzman et al., 1997; Stubbs et al., 1996; van Stratum et al., 1978).
These results suggest that energy density plays a more significant role than
fat per se in the short-term regulation of food intake.
During overfeeding, fat may be slightly more efficiently used than
carbohydrate (Horton et al., 1995), but in one study, no difference was
seen (McDevitt et al., 2000). Thus, high fat diets are not intrinsically fatten-
ing, calorie for calorie, and will not lead to obesity unless excess total
energy is consumed. It is apparent, however, that with the consumption of
high fat diets by the free-living population, energy intake does increase,
therefore predisposing to increased weight gain and obesity if activity level
is not adjusted accordingly (see Table 11-1). While many of the short-term
studies showed a more dramatic effect on weight reduction with reduced
fat intake, the long-term studies showed weight loss as well.
Conclusions. Epidemiological studies provide mixed results on the
question of whether high fat (low carbohydrate) diets predispose to over-

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weight and obesity and promote weight gain. However, a number of short-
term studies suggest mechanisms whereby high fat intake could promote
weight gain in the long-term. In addition, short- and long-term interven-
tion studies provide evidence that reduced fat intake is accompanied by
reduced energy intake and therefore moderate weight reduction or pre-
vention of weight gain. For these reasons, it may be concluded that higher
fat intakes are accompanied with increased energy intake and therefore
increased risk for weight gain in populations that are already disposed to
overweight and obesity, such as that of North America.
Risk of CHD
Epidemiological Evidence. In populations that consume very low fat
diets, such as those of rural Asia and Africa, the prevalence of CHD is low
(Campbell et al., 1998; Singh et al., 1995; Tao et al., 1989; Walker and
Walker, 1978). This fact has led to the concept that low fat diets will pro-
tect against CHD. However, this conclusion must be drawn with caution
when it is applied to societies in which dietary and exercise habits differ
markedly from societies in rural Asia and Africa. In the latter societies,
people are highly active and lean (Singh et al., 1995; Walker and Walker,
1978). Both of these factors independently reduce risk for CHD and could
offset any potentially detrimental effects of very low fat diets. For this
reason, the effects of low fat diets must be viewed in the context of current
societal habits in the United States and Canada and of changing habits in
developing countries. Furthermore, in more recent years it has become
clear that the relationship between fat intake and CHD is related more to
the quality of fat than to the quantity. The relationship is clearly shown by
cross-population studies. For example, some Mediterranean populations
consume diets that are high in total fat and unsaturated fatty acids but low
in saturated fatty acids; in these populations, rates of CHD are relatively
low (Keys et al., 1980, 1984). In contrast, in northern Europe, where
intakes of saturated fatty acids are high, so are rates of CHD (Keys et al.,
1980, 1984). Two epidemiological studies showed no relationship between
carbohydrate intake and LDL cholesterol concentration (Fehily et al.,
1988; Tillotson et al., 1997).
In several recent, long-term prospective studies of diet and chronic
disease, rates of CHD did not substantially differ across populations that
consumed approximately 25 to 45 percent of energy from fat (Ascherio et
al., 1996; Hu et al., 1997). Men who developed CHD were shown to consume
a slightly higher percentage of energy from fat (34.7 percent) compared
with those who did not develop CHD (33.3 percent); however, this small
difference in fat intake may not be significant since intake was based on a

798 DIETARY REFERENCE INTAKES
24-hour recall, and the data were not adjusted for energy intake (McGee
et al., 1984). Furthermore, Hawaiians, who have a higher incidence of
CHD than Japanese living in Hawaii, consumed more energy from fat
(35 percent) than the Japanese (31 percent) (Bassett et al., 1969). It has
been reported that those who developed CHD consumed slightly less
energy from carbohydrate compared to those who did not develop CHD
(Kushi et al., 1985; McGee et al., 1984) (Table 11-7). Other studies showed
no significant association between risk of CHD and total carbohydrate or
sugar intake (Bolton-Smith and Woodward, 1994; Liu et al., 1982, 2000).
Interventional Evidence. Increasing fat intake, as a result of increased
saturated fat intake, has been shown to increase LDL cholesterol concen-
trations (Table 11-2), and therefore risk of CHD. Intervention studies that
have investigated the effect of carbohydrate intake on LDL cholesterol
concentration have shown mixed results (Table 11-3). Two intervention
studies agree with the findings of West and colleagues (1990) in that LDL
cholesterol concentration increased when the percent of energy from car-
bohydrate was decreased from 55 to 31 percent (Borkman et al., 1991)
and 59 to 41 percent (Marckmann et al., 2000). However, in other studies
in which saturated fatty acids have remained constant, varying the percent-
age of total fat was found to not alter the LDL cholesterol concentration
(Garg et al., 1994; Grundy et al., 1988).
Yu-Poth and colleagues (1999) conducted a meta-analysis on 37 inter-
vention studies that evaluated the effects of the National Cholesterol Edu-
cation Programâs Step I and Step II dietary interventions on various cardio-
vascular disease risk factors. Reductions in plasma total cholesterol and
LDL cholesterol concentrations were significantly correlated with reduc-
tions in percentages of total dietary fat, but these also included a decrease
in saturated fatty acids. Similarly, individuals who consumed the Dietary
Approaches to Stop Hypertension diet, which contains 27 percent of energy
from fat and only 7 percent of energy from saturated fat, had reduced
total and LDL cholesterol concentrations (Obarzanek et al., 2001b). Singh
and colleagues (1992) reported that mortality from CHD and other causes
was significantly lower when patients with acute myocardial infarction were
fed a reduced fat diet.
The increase in LDL cholesterol concentration observed with increased
fat intake is due to the strong positive association between total fat and
saturated fat intake and the weak association between total fat and poly-
unsaturated fat intake (Masironi, 1970; Stamler, 1979). This association is
also observed in Appendix Tables K-4, K-5, K-7, and K-8. As shown in many
studies, saturated fatty acids raise LDL cholesterol concentrations (see
Chapter 8), whereas unsaturated fatty acids do not. In fact, n- 6 poly-
unsaturated fatty acids reduce serum LDL cholesterol concentrations some-

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M ACRONUTRIENTS AND HEALTHFUL DIETS
what compared with carbohydrate (Hegsted et al., 1993; Mensink and Katan,
1992). The adverse effects of saturated fats are discussed in Chapter 8.
It has been postulated that a high fat intake predisposes to a pro-
thrombotic state, which contributes to venous thrombosis, coronary
thrombosis, or thrombotic strokes (Barinagarrementeria et al., 1998; Kahn
et al., 1997; Salomon et al., 1999). Consumption of diets high in fat (42 or
50 percent) have been shown to increase blood concentrations of the
prothrombotic markers, blood coagulation factor VII (VIIc), and activated
factor VII (VIIa) (Bladbjerg et al., 1994; Larsen et al., 1997). The concen-
tration of factor VII is associated with increased risk of CHD (Kelleher,
1992). Furthermore, a significant and positive association was found between
the level of dietary fat and factor VIIc concentration (Miller et al., 1989).
Relation of Intakes of Saturated Fatty Acids and Total Fat. When fat is con-
sumed in typical foods it contains a mixture of saturated, polyunsaturated,
and monounsaturated fatty acids. Even when the content of saturated fatty
acids in consumed fats is relatively low, the intakes of these fatty acids can
be high with high fat intakes. For example, if all of the dietary fats con-
sumed were low in saturated fatty acids (e.g., 20 percent of fat energy), a
total fat intake of 35 percent of total energy would yield a saturated fatty
acid intake of 7 percent of total energy. Consumption of a variety of dietary
fats would likely result in an even higher percentage of saturated fatty
acids. Thus, in practical terms, it would be difficult to avoid high intakes of
saturated fatty acids for most persons if total fat intakes exceeded 35 per-
cent of total energy. This fact is revealed by attempts to create a variety of
heart-healthy menus (National Cholesterol Education Program, 2001).
Moreover, data from CSFII show that with increased fat intake, there tends
to be a greater increase in saturated fatty acid intake relative to poly-
unsaturated fatty acid intake (Appendix Tables K-4, K-5, K-7, K-8; Masironi,
1970; Stamler, 1979). It should be pointed out, however, that when replac-
ing saturated fatty acid intake with carbohydrate, there is no effect on the
total cholesterol:HDL cholesterol ratio (Mensink and Katan, 1992).
Conclusions. A few case-control studies have shown an association between
total fat intake and risk for CHD. However, a detailed evaluation of these
studies shows that it is not possible to separate total fat intake from saturated
fatty acid intake, which is known to raise LDL cholesterol concentrations.
Unsaturated fatty acids, which do not raise LDL cholesterol concentra-
tions compared with carbohydrate, have not been implicated in risk for
CHD through adverse effects on lipids or other risk factors. Nonetheless,
practical efforts to create âheart-healthyâ menus reveal that intakes of total
fat exceeding 35 percent of total energy result in unacceptably high intakes

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Epidemiological Evidence. In several population studies, investigators
have attempted to determine the contribution of total fat intake to either
insulin sensitivity or diabetes. These analyses are difficult to interpret because
of the multiplicity of potential confounding variables. Nevertheless, several
studies have reported an association between higher fat intakes and insulin
resistance as indicated by high fasting insulin concentration, impaired
glucose tolerance, or impaired insulin sensitivity (Lovejoy and DiGirolamo,
1992; Marshall et al., 1991; Mayer et al., 1993), as well as to the develop-
ment of type 2 diabetes (West and Kalbfleisch, 1971). A number of studies,
however, have not shown this association (Coulston et al., 1983; Liu et al.,
1983; SalmerÃ³n et al., 2001). In the Insulin Resistance Atherosclerosis
Study, total fat intake univariately correlated with less insulin sensitivity
(Mayer-Davis et al., 1997); however, in multiple regression analyses, the
presence of obesity appeared to be a confounding variable. Lovejoy and
DiGirolamo (1992) likewise found intercorrelations among insulin resis-
tance, total fat intake, and obesity. In contrast, Larsson and coworkers
(1999) found no evidence of independent effects of diet on insulin secre-
tory or sensitivity among 74 postmenopausal women. Although several
studies suggest an association between total fat intake and the presence of
insulin resistance (Lovejoy, 1999; Vessby, 2000), the degree to which the
relationship is mediated by obesity remains uncertain. Decreased physical
activity is also a significant predictor of higher postprandial insulin con-
centrations and may confound some studies (Feskens et al., 1994; Parker
et al., 1993).
Interventional Evidence. A number of metabolic and intervention studies
have examined the relationships among fat intake, fasting glucose and
insulin concentrations, areas under curves for plasma glucose and insulin
concentrations, insulin sensitivity, glucose effectiveness, and glucose disposal
rates (Table 11-8). Several studies reported that diets containing 35 per-
cent fat were accompanied by more impaired glucose tolerance than diets
containing 25 percent fat or less (Fukagawa et al., 1990; Jeppesen et al.,
1997; Straznicky et al., 1999; Swinburn et al., 1991). Coulston and coworkers
(1983) found that a diet containing 41 percent fat led to significantly
higher concentrations of insulin in response to meals compared with a
diet containing 21 percent fat, but there were no alterations in fasting
concentrations. In other studies, no effect on measures of glucose toler-
ance were reported when diets varied in fat content from 11 to 30 (Leclerc
et al., 1993) or 20 to 50 percent fat (Abbott et al., 1989; Borkman et al.,
1991; Howard et al., 1991; Thomsen et al., 1999). When the diet was high
in fat (50 percent of energy), the area under the curve for plasma glucose
and insulin concentration was lower than when the diet had a low fat
content (25 percent of energy) (Yost et al., 1998). In this study, the decreased

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M ACRONUTRIENTS AND HEALTHFUL DIETS
Glucose
Area Under Area Under Disposal/
the Curve the Curve Insulin Glucose Disappearance
for Glucose for Insulin Sensitivity Effectiveness Rate
Increasede Increasede Decreasedd
NSC ND
NSC NSC ND ND ND
Increased d
NSC ND ND ND
Decreasede Decreasedc ND ND ND
Increasede Decreased b
NSC ND ND
ND NSC NSC NSC ND
ND ND ND ND ND
including a reduction of total fat intake from 34 to 27 percent of energy
reduced the incidence of type 2 diabetes by 58 percent. Thus, there is no
definitive evidence from metabolic and interventional studies that higher
fat intakes impair insulin sensitivity in humans as they do in various labora-
tory animals. Any suggestive links between fat intake and either insulin
secretion or sensitivity may be mediated through confounding factors, such
as body-fat content, making it difficult to detect any independent contri-
bution of total fat intake to insulin sensitivity.
Conclusions. Although high fat diets can induce insulin resistance in
rodents, investigations in humans fail to confirm this effect. Moreover, an

808 DIETARY REFERENCE INTAKES
association between dietary fat intake and risk for diabetes has been
reported in some epidemiological studies, but this association is most likely
confounded by various factors, such as obesity and glycemic index.
Risk of Cancer
High intakes of dietary fat have been implicated in the development
of cancer, especially cancer of the lung, breast, colon, and prostate gland.
Early support for this theory comes from laboratory animal and cross-
cultural studies. The latter were based largely on international food dis-
appearance data and migrant and time trend studies. In recent years, the
theory that a diet high in fat predisposes to certain cancers has been weak-
ened by additional epidemiological studies. Early cross-cultural and case-
control studies reported strong associations between total fat intake and
breast cancer (Howe et al., 1991; Miller et al., 1978; vanât Veer et al.,
1990), yet a number of epidemiological studies, most in the last 15 years,
have found little or no association between fat intake and breast cancer
(Hunter et al., 1996; Jones et al., 1987; Kushi et al., 1992; van den Brandt
et al., 1993; Velie et al., 2000; Willett et al., 1987, 1992). A meta-analysis of
23 studies yielded a relative risk of 1.01 and 1.21 from cohort and case-
control studies, respectively (Boyd et al., 1993).
Total fat intake in relation to colon cancer has strong support from
animal studies (Reddy, 1992). However, evidence from epidemiological
studies has been mixed (De Stefani et al., 1997b; Giovannucci et al., 1994;
Willett et al., 1990). Howe and colleagues (1997) reported no association
between fat intake and risk of colorectal cancer from the combined analysis
of 13 case-control studies.
Epidemiological studies tend to suggest that dietary fat intake is not
associated with prostate cancer (Ramon et al., 2000; VeierÃ¸d et al., 1997b).
Giovannucci and coworkers (1993), however, reported a positive association
between total fat consumption, primarily animal fat, and risk of advanced
prostate cancer. Findings on the association between fat intake and lung
cancer have been mixed (De Stefani et al., 1997a; Goodman et al., 1988;
VeierÃ¸d et al., 1997a; Wu et al., 1994).
Risk of Nutrient Inadequacy or Excess
Diets High in Fat. With increasing intakes of carbohydrate, and there-
fore decreasing fat intakes, there is a trend towards reduced consumption
of dietary fiber, folate, and vitamin C (Appendix K). With higher fat
intakes, it is difficult to create practical high fat menus that do not contain
unacceptably high amounts of saturated fatty acids (National Cholesterol
Education Program, 2001).

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Diets Low in Total Sugars. Micronutrient inadequacy can occur when
sugars intake is very low (less than 4 percent of total energy) (Bolton-
Smith and Woodward, 1995) because many foods that are abundant in
micronutrients, such as fruits and dairy products, also contain naturally
occurring sugars. A wide variety of foods from different food groups are
needed to meet nutrient requirements. Because sugars are important for
the palatability of foods, the complete omission of sugars from the diet
could endanger overall nutrient adequacy by leading to low total energy
intake, as well as low micronutrient intakes (Bolton-Smith, 1996). Although
reduced nutrient intakes have been reported, adverse affects on health
have not. Individuals with fructose intolerance, a condition caused by
fructose-1-phosphate aldolase deficiency, strictly avoid foods containing
fructose and sucrose and yet remain in good health (Burmeister et al., 1991).
AMDRs for Adults
When fat intakes are low and carbohydrate intakes are high, interven-
tion studies, with the support of epidemiological studies, demonstrate a
reduction in plasma HDL cholesterol concentration, an increase in the
plasma total cholesterol:HDL cholesterol ratio, and an increase in plasma
triacylglycerol concentration, which are all consistent with an increased
risk of CHD. Conversely, many interventional studies show that when fat
intake is high, many individuals consume additional energy, and therefore
gain additional weight. Weight gain on high fat diets can be detrimental to
individuals already susceptible to obesity and can worsen the metabolic
consequences of obesity, particularly the risk of CHD. Moreover, high fat
diets are usually accompanied by increased intakes of saturated fatty acids,
which can raise plasma LDL cholesterol concentrations and further increase
risk for CHD. Based on the apparent risk for CHD that may occur on low
fat diets, and the risk for increased energy intake and therefore obesity
with the consumption of high fat diets, the AMDR for fat and carbohydrate is
estimated to be 20 to 35 and 45 to 65 percent of energy, respectively, for
all adults. By consuming fat and carbohydrate within these ranges, the risk
for obesity, as well as for CHD and diabetes, can be kept at a minimum.
Furthermore, these ranges allow for sufficient intakes of essential nutri-
ents while keeping the intake of saturated fatty acids at moderate levels.
There is no lower limit of intake and no known adverse effects with
the chronic consumption of Dietary Fiber or Functional Fiber (Chapter 7).
Therefore, an AMDR is not set for Dietary, Functional, or Total Fiber.

810 DIETARY REFERENCE INTAKES
Maximal Intake Level for Added Sugars
Data from various national surveys show that increasing intakes of
added sugars is associated with a decline in the consumption of certain
micronutrients, thus increasing the prevalence of those consuming below
the EAR or the AI. While such trends exist, it is not possible to determine a
defined intake level at which inadequate micronutrient intakes occur. Fur-
thermore, at very low or very high intakes, unusual eating habits most
likely exist that allow for other factors to contribute to low micronutrient
intakes. Based on the available data, no more than 25 energy from added
sugars should be comsumed by adults. A daily intake of added sugars that
individuals should aim for to achieve a healthy diet was not set. Total
sugars intake can be lowered by consuming primarily sugars that are natu-
rally occurring and present in micronutrient-rich foods, such as milk, dairy
products, and fruits, while at the same time limiting consumption of added
sugars from foods and beverages that contain minimal amounts of micro-
nutrients, such as soft drinks, fruitades, and candies.
Low Fat, High Carbohydrate Diets of Children
Fat Oxidation
Jones and colleagues (1998) reported a significantly greater fat
oxidation in children (aged 5 to 10 years, n = 12) than in adults (aged 20
to 30 years, n = 6). Breath 13CO2 was measured in 12 children and 6 men
following an oral bolus dose of [1-13C]palmitic acid (10 mg/kg of body
weight) consumed with a test meal. Breath 13CO2 excretion was less in the
men (35.1 percent of absorbed dose, P = 0.005) than in the children
(57.0 percent of absorbed dose). The children exhibited greater fat oxida-
tion in the postabsorptive state (2.43 g/h) and postprandial (11.89 g/6 h)
states than the men (0.93 g/h postabsorptive, 9.86 g/6 h postprandial).
The children also had greater fat oxidation compared with women studied
previously by these investigators (0.53 g/h postabsorptive, 0.03 g/6 h post-
prandial) (Murphy et al., 1995).
Growth
Most studies have reported no effect of the level of dietary fat on
growth when energy intake is adequate (Boulton and Magarey, 1995;
Fomon et al., 1976; LagstrÃ¶m et al., 1999; Lapinleimu et al., 1995;
Niinikoski et al., 1997a, 1997b; Obarzanek et al., 1997; Shea et al., 1993).
Two well-controlled trials demonstrated that a diet providing less than
30 percent energy from fat does not result in adverse effects on growth in

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M ACRONUTRIENTS AND HEALTHFUL DIETS
children up to 8 years of age (Lapinleimu et al., 1995; Niinikoski et al.,
1997a, 1997b). A cohort study with a 25-month follow-up showed that there
was no difference in stature or growth of children aged 3 to 4 years at
baseline across quintiles (27 to 38 percent) of total fat intake (Shea et al.,
1993). The Special Turku Coronary Risk Factor Intervention Project showed
no difference in growth of children 7 months to 5 years of age when they
consumed 21 to 38 percent fat (LagstrÃ¶m et al., 1999). Niinikoski and
coworkers (1997a) reported that 1-year-old children who consistently con-
sumed low fat diets (less than 28 percent) grew as well as children with
higher fat intakes. A cohort study showed that children aged 2 years in the
lower tertile of fat intake (less than 30 percent) had a height and weight
similar to that of the higher fat intake groups (Boulton and Magarey,
1995).
A few studies have observed impaired growth among hypercholsterolemic
children who were advised to consume 30 percent or less of energy from
fat. However, the energy intake was also reduced (Lifshitz and Moses,
1989) or not reported (Hansen et al., 1992). In a group of Canadian
children 3 to 6 years of age, a fat intake of less than 30 percent of energy
was associated with an odds ratio of 2.3 for weight-for-age below the 50th
percentile at 6 years of age (Vobecky et al., 1995). A comprehensive evalu-
ation of the effect of diet-related variables on the growth of children under
6 years of age from 18 Latin American countries (FAO/WHO, 1996) demon-
strated that diets providing less than 22 percent energy from fat and with
less than 45 percent of total fat from animal fat were related to low birth
weight, underweight, and stunting (height-for-age â¤ 2 standard deviations)
(Uauy et al., 2000). The dietary determinants that best explained low birth
weight were energy, protein, and animal fat, suggesting that high-quality
animal protein and associated nutrients are important for growth and
development.
Risk of Nutrient Inadequacy or Excess
Diets High in Carbohydrate and Low in Fats. Because the diets of young
children are less diversified than that of adults, the risk of inadequate
micronutrient intake is increased in these children. A cohort of 500 children
aged 3 to 6 years showed that those who consumed less than 30 percent of
energy from fat consumed less vitamin A, vitamin D, and vitamin E com-
pared with those who consumed higher intakes of fat (30 to 40 percent)
(Vobecky et al., 1995). Calcium intakes decreased by more than 100 mg/d
for 4- and 6-year-old children who consumed less than 30 percent of energy
from fat (Boulton and Magarey, 1995). LagstrÃ¶m and coworkers (1997,
1999), however, did not observe reduced intakes of micronutrients in chil-
dren with low fat intakes (26 percent).

812 DIETARY REFERENCE INTAKES
The Dietary Intervention Study in Children (DISC), a multi-center,
randomized trial of children 8 to 10 years of age, demonstrated that reduc-
ing the intake of fat to 28 percent of energy over a 3-year period increased
the percentage of children not meeting the RDA for vitamin E and zinc;
however, no biochemical evidence of deficiency of these nutrients was
found (Obarzanek et al., 1997). Tonstad and Sivertsen (1997) observed no
reduced intake of micronutrients with diets providing 25 percent of energy
as fat. Nicklas and coworkers (1992) reported reduced intakes of certain
micronutrients by 10-year-old children who consumed less than 30 per-
cent of energy as fat; however, this level of fat intake was associated with
marked increased intakes of candy. It has been suggested that children
who consume a low fat diet can meet their micronutrient recommendation
by appropriate selection of certain low fat foods (Peterson and Sigman-
Grant, 1997). This is especially true for older children whose diets are
typically more diverse.
The tables in Appendix K show the intakes of nutrients at various
intake levels of carbohydrate. With increasing intakes of carbohydrate, and
therefore decreasing intakes of fat, the intake levels of calcium and zinc
markedly decreased in children 1 to 18 years of age (Appendix Tables K-1
through K-3).
Diets High in Added Sugars. Several surveys have evaluated the impact
of added sugars intake on micronutrient intakes in children (Table 11-5).
Gibson (1997) examined data from the U.K. National Diet and Nutrition
Survey of Children Aged 1.5 to 4.5 Years (boys, n = 848; girls, n = 827) and
found evidence of a nutrient dilution effect by nonmilk extrinsic sugars
(NMES). Children consuming the highest concentrations of NMES
(greater than 24 percent of energy) had intakes of most micronutrients
that were between 6 and 20 percent below average. Gibson (1997) con-
cluded that the inverse association of NMES with micronutrient intakes
was of most significance for the 20 percent of children with the diets
highest in NMES (24.9 percent of energy for boys and 24.5 percent of
energy for girls).
In a study of British adolescents, reduced intakes of calcium, phosphorus,
iron, vitamin A, vitamin D, and folic acid were associated with increased
sugars intakes (mean added sugars intake for the high sugars consumers
was 122 g/d for boys and 119 g/d for girls) (Rugg-Gunn et al., 1991). In a
smaller survey (n = 143), added sugars intakes at levels as high as 27 per-
cent of energy did not have a significant impact on micronutrient intakes
(Nelson, 1991).
Similar to that observed for adults using data from NHANES III,
increasing the added sugars intake by every 5th percentile tended to be
associated with reduced intakes of certain micronutrients, including

813
M ACRONUTRIENTS AND HEALTHFUL DIETS
calcium, vitamin A, iron, and zinc (Appendix Tables J-1 through J-3, J-6,
and J-7). This reduction in micronutrient intake was most significant when
added sugars intake levels exceeded 25 percent of energy.
From 1989 to 1995, energy intakes increased for U.S. children aged 2
to 17 years primarily due to increased carbohydrate consumption. Bever-
ages, particularly soft drinks, were important contributors to the increased
carbohydrate consumption. During this period, micronutrient intakes
(except for iron) did not increase and calcium intakes decreased. This was
attributed to the fact that increased energy was largely obtained from soft
drinks, which do not add nutrients and displace milk in childrenâs diets,
with negative consequences for total diet quality (Morton and Guthrie, 1998).
Children who were high consumers of nondiet soft drinks had lower
intakes of riboflavin, folate, vitamin A, vitamin C, calcium, and phosphorus
in comparison with children who were nonconsumers of soft drinks
(Harnack et al., 1999). Several of these nutrients (folate, vitamin A, and
calcium) have been identified in national surveys as âshortfallâ or âproblemâ
nutrients among various age and gender groups (ARS, 1998). Ballew and
colleagues (2000) demonstrated that in U.S. children, milk consumption
was positively associated with the likelihood of achieving recommended
vitamin A, vitamin B12, folate, calcium, and magnesium intakes in all age
groups. Juice (100 percent fruit or vegetable juice) consumption was posi-
tively associated with achieving vitamin C and folate recommended intakes
in all age groups, as well as magnesium intake among children aged 6 years
and older. Soft drink intake was negatively associated with achieving rec-
ommended vitamin A intake in all age groups, calcium in children younger
than 12 years of age, and magnesium in children 6 years of age and older.
Others have shown that children who consumed milk at the noon
meal had the highest daily intakes of vitamin A, vitamin E, calcium, and
zinc, whereas the opposite was true for children who consumed soft drinks
and tea (Johnson et al., 1998). Hence, beverages that are major contributors
of the naturally occurring sugars, such as lactose and fructose, in the diet
(e.g., milk and fruit juice) have been positively associated with nutrient
adequacy, while beverages that are the principal source of added sugars in
the diet (e.g., soft drinks) have been negatively associated with nutrient
adequacy in the diets of U.S. children and adolescents (Ballew et al., 2000;
Johnson et al., 1998).
Diets High in Total Sugars. The findings from three surveys on the
relationship between total sugars intake and micronutrient intake in
children are mixed (Table 11-6). Gibson (1993) did not observe reduced
micronutrient intakes when total sugars intake exceeded 25 percent of
energy. Nicklas and coworkers (1996) reported that the percent of chil-
dren meeting the RDA for only niacin and zinc was significantly reduced

814 DIETARY REFERENCE INTAKES
when the intake of total sugars exceeded 31 percent of energy. A linear
reduction in several micronutrients was observed with increasing total
sugars intake (Farris et al., 1998).
High Fat, Low Carbohydrate Diets of Children
Risk of Obesity
In the United States and Canada, there is evidence that children are
becoming progressively overweight (Flegal, 1999; Gortmaker et al., 1987;
Tremblay and Willms, 2000; Troiano et al., 1995). Furthermore, Serdula
and coworkers (1993) reviewed a number of longitudinal studies with vary-
ing cut-off levels for obesity and concluded that 26 to 41 percent of obese
preschool children and 42 to 63 percent of obese school-age children
became obese adults. Clinical evidence of disease associated with excess
body weight, reduced physical activity, or high dietary fat intakes, however,
are generally absent. The evidence for a role of dietary fat intakes in pro-
moting higher energy intakes and thus promoting obesity in young chil-
dren is conflicting.
A positive trend in energy intake was associated with an increased
percent of energy from fat for children up to 8 years of age (Boulton and
Magarey, 1995). A positive correlation between fat intake and fat mass has
been reported for boys 4 to 7 years of age (Nguyen et al., 1996). A lack of
effect of dietary fat on BMI and adiposity, however, has been reported for
children 1.5 to 4.5 years of age (Atkin and Davies, 2000; Davies, 1997).
The DISC trial found no difference in BMI for children 8 to 10 years
of age who consumed diets containing 29 or 33 percent fat over a 3-year
period (Lauer et al., 2000). However, several studies showed a positive
correlation between dietary fat intake and body fatness in children 8
to 12 years of age (Maffeis et al., 1996; Obarzanek et al., 1994; Ricketts,
1997). The average fat intake of nonobese children was measured to be 31
to 34 percent for children 9 to 11 years old, whereas the average fat intake
of obese children was 39 percent of energy (Gazzaniga and Burns, 1993).
A positive association between fat intake and several adiposity indices were
observed, but only for up to 35 percent of energy (Maillard et al., 2000).
Other factors that have been associated with increased BMI include
physical activity.
Risk of CHD
Clinical studies have provided some evidence that serum cholesterol
concentration is modified in children the same way as in adults, with serum
total, LDL, and non-HDL cholesterol concentrations being increased by

815
M ACRONUTRIENTS AND HEALTHFUL DIETS
consuming diets higher in total fat (Lauer et al., 2000; Niinikoski et al.,
1996; Obarzanek et al., 2001a; Shannon et al., 1994; Simell et al., 2000;
Vartiainen et al., 1986). However, no significant association between
dietary fat and LDL cholesterol concentration was observed for boys and
girls (aged 8 to 10 years) consuming fat ranging from 10 to 50 percent of
energy (R = â0.04 to 0.14) (Kwiterovich et al., 1997). Furthermore, a
significant positive association between fat intake and total cholesterol con-
centration was observed in only two of five countries (Knuiman et al., 1983).
Another potential indicator for childrenâs future risk of CHD is the
presence of fatty streaks, which are found in the aortas of almost all chil-
dren over 3 years of age in North America (Holman et al., 1958), and
begin to appear in the coronary arteries about 5 to 10 years later than in
the aorta (Berenson et al., 1992; McGill, 1968; Stary, 1989; Strong et al.,
1992). The prevalence of aortic fatty streaks differs only slightly among
children and adolescents of all populations studied, regardless of the fre-
quency of atherosclerosis and coronary artery disease in adults of the
respective population (Holman et al., 1958; McGill, 1968). The absence of
a relation between aortic fatty streaks and the clinically relevant lesions of
atherosclerosis in epidemiological and histological studies has thus raised
questions on the clinical significance of fatty streaks in the aorta of young
children (Newman et al., 1995; Olson, 2000). The Pathobiological Deter-
minants of Atherosclerosis in Youth Study, however, has provided evidence
that an unfavorable lipoprotein pattern (i.e., elevated non-HDL cholesterol
and low HDL cholesterol concentrations), obesity, and hyperglycemia are
associated with raised fatty streaks in the coronary artery and abdominal
aorta in late teenage years (McGill et al., 2000a, 2000b). Similarly, the
Bogalusa Heart Study observed a positive association between LDL choles-
terol concentration and the percentage of surface with fatty streaks in the
aorta (Berenson et al., 1992). These findings are consistent with the
hypothesis of the progression of fatty streaks to fibrous plaques under
the influence of the prevailing risk factors for coronary artery disease
(McGill et al., 2000a, 2000b).
It is still unclear, however, how reduction in serum cholesterol con-
centration in childhood, if maintained, is associated with risk of CHD in
adulthood. In addition, there are still pivotal issues that must be examined
further, including the relationship between fatty streaks found in the arteries
of young children and the later appearance of raised lesions associated
with coronary vascular disease, the effects of dietary total fat modification
on predictive risk factors in children, the safety of the diet with respect to
total energy and micronutrients for the general population, and the long-
term health benefit of establishing healthy dietary patterns early in childhood.

816 DIETARY REFERENCE INTAKES
Risk of Nutrient Inadequacy or Excess
Appendix Tables K-1 through K-3 and K-6 provide data from CFSII on
the intake of various nutrients based on the level of carbohydrate intake. It
can been seen from these tables that as the level of carbohydrate intake
decreases, and therefore the level of fat increases, certain nutrients such as
folate and vitamin C markedly decrease. Furthermore, with increasing
levels of fat intake, the intake of saturated fat relative to linoleic acid intake
markedly increases.
AMDRs for Children
The evidence suggests that children have a higher fat oxidation rate
compared to adults, and that reduced intake of certain micronutrients can
occur with the consumption of low fat diets, whereas there is potential risk
of obesity with high fat intakes. High intakes of fat may promote increased
risk for CHD and obesity. Dietary fat provides energy, which may be
important for younger children with reduced food intakes, particularly
during the transition from a diet high in milk to a mixed diet. Thus, there
should be a transition from the high fat intake during infancy (55 and
40 percent of energy for the 0- to 6- and 7- to 12-months age groups,
respectively) (Chapter 8) to an AMDR for adults (20 to 35 percent of
energy). Therefore, it is estimated that the AMDR for fat intake is approxi-
mately 30 to 40 percent of energy for children 1 to 3 years of age and 25 to
35 percent of energy for children 4 to 18 years of age. The AMDR for
carbohydrate is the same as for adults (45 to 65 percent of energy). The
ranges of fat intake include intakes of saturated fat that should be consumed
at levels as low as possible while consuming a nutritionally adequate diet.
Maximal Intake Level for Added Sugars
As for adults, no more than 25 percent of energy from added sugars
should be consumed by children to ensure adequate micronutrient
intakes. For those children whose intake is above this level, added sugars
intake can be reduced by consuming sugars that are primarily naturally
occurring and present in foods such as milk, dairy products, and fruits,
which also contain essential micronutrients.
n-9 MONOUNSATURATED FATTY ACIDS
Approximately 20 to 40 percent of fat is consumed as n-9 mono-
unsaturated fatty acids, almost all of which is oleic acid (Appendix Tables
E-1 and E-8). Monounsaturated fatty acids are not essential fatty acids, but
they may have some benefit in the prevention of chronic disease. Although

817
M ACRONUTRIENTS AND HEALTHFUL DIETS
early research pointed to this potential benefit, most attention has been
given to it in the past decade.
Low n-9 Monounsaturated Fatty Acid Diets
Risk of CHD
Epidemiological Evidence. Population data on monounsaturated fatty
acid intake and risk of coronary heart disease (CHD) are limited. How-
ever, in long-term follow-up studies of the Seven Countries Study, higher
intakes of monounsaturated fatty acids were associated with decreased rates
of CHD mortality (Keys et al., 1986). Other reports indicate that mono-
unsaturated fatty acids have a neutral or beneficial effect on risk (Hu et al.,
1997; Kromhout and de Lezenne Coulander, 1984; Pietinen et al., 1997).
Interventional Evidence. Much work has been conducted and is ongoing
to identify the ideal substitute for saturated fat in a blood cholesterol-
lowering diet. The effects of a high monounsaturated fatty acid versus a
low fat, high carbohydrate diet on serum lipid and lipoprotein concentrations
have been a focus of considerable scientific inquiry. Eighteen well-
controlled clinical studies that compared the effects of substituting mono-
unsaturated fatty acids versus carbohydrate for saturated fat in a blood
cholesterol-lowering diet have recently been reviewed (Kris-Etherton et
al., 2000). In these studies, when on both high monounsaturated fat and
low fat, high carbohydrate diets, saturated fatty acids contributed to 4 to
12 percent of energy and dietary cholesterol varied from less than 100 up
to 410 mg/d. Diets high in monounsaturated fatty acids provided 17 to
33 percent of energy from monounsaturated fatty acids and contained
more total fat (33 to 50 percent energy) than the low fat, high carbohy-
drate diets (18 to 30 percent energy). The low fat, high carbohydrate diets
provided 55 to 67 percent of energy from carbohydrate. Compared to
baseline values, serum total cholesterol concentrations changed from â17
to +3 percent on the low fat, high carbohydrate diet, whereas it changed
from â20 to â3 percent on the high monounsaturated fatty acid diet. The
range of decrease in plasma low density lipoprotein (LDL) cholesterol
concentration was similar (â22 to +1 percent) among individuals on the
two diets. The change in serum triacylglycerol concentrations ranged from
â23 to +37 percent for individuals consuming the low fat, high carbo-
hydrate diets and from â43 to +12 percent for diets high in monounsaturated
fatty acids. Changes in high density lipoprotein (HDL) cholesterol con-
centrations ranged from â25 to +2 percent for individuals on the low fat,
high carbohydrate diets compared to a â9 to +6 percent change for indi-
viduals on diets high in monounsaturated fatty acids.

824 DIETARY REFERENCE INTAKES
1989). Oxidation products of lipids and proteins are found in athero-
sclerotic plaque and in macrophage foam cells. Compared with mono-
unsaturated fatty acids, in vitro susceptibility of LDLs to undergo oxidative
modification has been shown to increase with increased linoleic acid con-
tent in LDLs as a result of increased intakes of linoleic acid (Abbey et al.,
1993; Berry et al., 1991; Bonanome et al., 1992; Louheranta et al., 1996;
Reaven et al., 1991, 1993, 1994).
The mechanism whereby incorporation of polyunsaturated fatty acids
into LDLs enhances susceptibility of LDL oxidation has been studied
extensively (Chisolm and Steinberg, 2000; Jessup and Kritharides, 2000).
Nonetheless, the hypothesis suggesting that a diet rich in polyunsaturated
fat increases the polyunsaturated fatty acid content of LDL particles and
increases their susceptibility to oxidation, which in turn leads to athero-
sclerosis and CHD, still needs to be substantiated in human studies before
measures of oxidation can be used as adequate indicators of chronic
disease.
Risk of Inflammatory Disorders
There has been significant interest in the use of dietary n-6 fatty acids
to modulate inflammatory response. Î³-Linolenic acid (GLA, 18:3n-6) is the
â6 desaturase product of linoleic acid and is elongated to dihomo-Î³-linolenic
acid (DGLA, 20:3n-6). The â6 desaturase enzyme is the initial step in
desaturation of linoleic acid to arachidonic acid (see Figure 8-1). When
given as a dietary supplement, GLA has been found to reduce symptoms of
several chronic inflammatory diseases such as rheumatoid arthritis and
atopic dermatitis (Andreassi et al., 1997; Leventhal et al., 1993, 1994; Lovell
et al., 1981; Tate et al., 1989; Zurier et al., 1996). Even though GLA is the
precursor to arachidonic acid, human neutrophils contain an elongase
enzyme that converts GLA to DGLA, but they lack the â 5 desaturase
needed to form arachidonic acid. As a result, GLA supplementation results
in accumulation of DGLA, but not arachidonic acid, and a reduction in
leukotriene B4 production in neutrophils (Chilton-Lopez et al., 1996;
Johnson et al., 1997; Ziboh and Fletcher, 1992). However, plasma arachidonic
acid concentrations increase after GLA supplementation (Johnson et al.,
1997), and this could have adverse implications for other problems such as
platelet aggregation (Rodier et al., 1993).
Risk of Cancer
An 8-year controlled clinical trial of 846 men demonstrated a signifi-
cant increase in fatal carcinomas when the amount of n-6 polyunsaturated
fatty acids fed was 15 percent of energy compared to 4 percent of energy

825
M ACRONUTRIENTS AND HEALTHFUL DIETS
(Pearce and Dayton, 1971). Epidemiological studies, however, suggest that
n-6 polyunsaturated fatty acids are not associated (or have an inverse
relationship) with cancer. Howe and coworkers (1990) analyzed 12 case-
control studies conducted prior to 1990 and determined that the relative
risk of breast cancer for an increment of 45 g of polyunsaturated fat per
day was only 1.25. More recent case-control and prospective studies fur-
ther support the minimal effect of n-6 polyunsaturated fatty acids on breast
cancer risk (MÃ¤nnistÃ¶ et al., 1999; Toniolo et al., 1994). A similar relation-
ship has been reported for linoleic acid intake and prostate cancer
(Giovannucci et al., 1993; Schuurman et al., 1999). A meta-analysis of
7 cohort studies (Hunter et al., 1996) and a combined analysis of 12 case-
control studies (Howe et al., 1990) consistently found no relationship
between polyunsaturated fats or vegetable fats and risk of breast cancer.
The range of intake of polyunsaturated fat was sufficiently large in these
combined studies to comfortably conclude that the epidemiological evi-
dence largely contradicts the animal studies; at least to date, no association
between polyunsaturated fat, mainly n-6 fatty acids, and risk of breast
cancer has been detected. Furthermore, in a review of the literature and
meta-analyses of case-controlled and prospective epidemiological studies,
Zock and Katan (1998) concluded that it was unlikely that high intakes of
linoleic acid substantially raise the risk of breast, colorectal, or prostate
cancer.
Risk of Nutrient Excess
High intakes of linoleic acid can inhibit the formation of long-chain
n-3 polyunsaturated fatty acids from Î±-linolenic acid, which are precursors
to the important eicosanoids (see Chapter 8).
Acceptable Macronutrient Distribution Range
Based on the median energy intakes for each age group (Appendix
Table E-1), a minimum intake of 5 percent of energy from linoleic acid
would be needed to meet the AI (see Chapter 8). An upper boundary of
10 percent of energy is estimated based on the following information:
(1) the highest intake of n-6 polyunsaturated fatty acids for individuals in
North America is approximately 10 percent of energy, (2) there is not a
large body of epidemiological evidence that demonstrates the long-term
safety of n-6 polyunsaturated fatty acid intakes exceeding 10 percent of
energy from typical mixed diets, and (3) evidence from human studies
demonstrates that enrichment of lipoproteins and cell membranes with
n-6 polyunsaturated fatty acids contributes to a pro-oxidant state, thus

826 DIETARY REFERENCE INTAKES
suggesting caution for recommending intakes that exceed 10 percent of
energy. For these reasons, an Acceptable Macronutrient Distribution Range
(AMDR) is estimated to be 5 to 10 percent of energy for children and
adults.
n-3 POLYUNSATURATED FATTY ACIDS
Low n-3 Polyunsaturated Fatty Acid Diets
Risk of CHD and Stroke
Growing evidence suggests that dietary n-3 polyunsaturated fatty acids
(eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) reduce
the risk of coronary heart disease (CHD) and stroke. n-3 Polyunsaturated
fatty acids may reduce CHD risk through a multitude of mechanisms by
(1) preventing arrhythmias (Billman et al., 1999; Kang and Leaf, 1996;
McLennan, 1993), (2) reducing atherosclerosis (von Schacky et al., 1999),
(3) decreasing platelet aggregation by inhibiting the production of throm-
boxane A2 (Harker et al., 1993), (4) decreasing plasma triacylglycerol con-
centration (Harris, 1989), (5) slightly increasing high density lipoprotein
(HDL) cholesterol concentration and decreasing triacylglycerol concen-
tration (Harris, 1989, 1997), (6) modulating endothelial function (De
Caterina et al., 2000), (7) decreasing proinflammatory eicosanoids (James
et al., 2000), and (8) moderately decreasing blood pressure (Morris, 1994).
Epidemiological Evidence. Many of the epidemiological studies used fish
or fish oil intake as a surrogate for n-3 polyunsaturated fatty acid intake.
The amounts of n-3 fatty acids vary greatly in fish, however, and unless the
amounts of n-3 fatty acids are known, any conclusions are open to question.
Furthermore, other components in fish may have effects that are similar to
n-3 fatty acids and therefore may confound the results. Early epidemiological
studies of Greenland Eskimos suggested that diets high in n-3 fatty acids,
predominantly EPA and DHA, might protect against CHD (Bang et al.,
1976; Dyerberg and Bang, 1979). Subsequent observational epidemiological
studies have shown mixed results. In the Zutphen study, eating fish one or
two times per week was associated with a significant reduction in CHD
mortality (Kromhout et al., 1985). A similar result was found in Rotterdam
that compared older people who ate fish with those who did not (Kromhout
et al., 1995). In three cohorts from the Seven Countries Study, the con-
sumption of fatty fish, but not total fish or lean fish, was associated with a
34 percent decrease in CHD mortality (Oomen et al., 2000). In the
Chicago Western Electric Study, eating more than 35 g/d of fish resulted
in decreased CHD mortality, mainly of the nonsudden death type (Daviglus

828 DIETARY REFERENCE INTAKES
but not hemorrhagic stroke (mainly among women who did not take
aspirin regularly) (Iso et al., 2001). In contrast, in the Chicago Western
Electric Study and the Physiciansâ Health Study, fish intake was not signifi-
cantly associated with decreased stroke risk (Morris et al., 1995; Orencia et
al., 1996).
Nonclinical Interventional Evidence. Supplementation with fish oil, which
is high in EPA and DHA, reduces triacylglycerol concentrations; low density
lipoprotein (LDL) and HDL cholesterol concentrations are either increased
or unchanged (Ã gren et al., 1996; Axelrod et al., 1994; Bhathena et al.,
1991; BÃ¸naa et al., 1992; DeLany et al., 1990; Eritsland et al., 1994a;
Haglund et al., 1990; Lungershausen et al., 1994; Mori et al., 1991; Nelson
et al., 1997a; Sanders and Hinds, 1992; Saynor and Gillott, 1992; Schmidt
et al., 1992).
Data from studies on the effects of EPA and DHA as a percent of
energy on blood lipid concentrations in healthy individuals are presented
in Table 11-10. In general, EPA+DHA intake is associated with small
increases in LDL and HDL cholesterol concentrations and a significant
decrease in triacylglycerol concentrations (Harris, 1997).
The consumption of 3.65 to 6 g/d of n-3 polyunsaturated fatty acids
inhibits platelet aggregation, which in turn prevents the risk of CHD (Mori
et al., 1997; Tremoli et al., 1995). Some studies, however, did not show an
effect on platelet aggregation after the consumption of 4.5 to 6 g/d of
EPA+DHA (Nelson et al., 1997b; Turini et al., 1994).
Randomized, Controlled Clinical Trials Evidence. There are four random-
ized, controlled clinical trials that show a benefit of fish, fish oils, or
Î±-linolenic acid on CHD prevention. In the Diet and Reinfarction Trial
(DART), male myocardial infarction (MI) survivors were encouraged to
increase their oily fish intake to 200 to 400 g/wk in order to increase EPA
and DHA intake. Over a 2-year period, this resulted in a significant reduc-
tion in total mortality, with the greatest benefit in a lower rate of fatal MI
(Burr et al., 1989a, 1989b). In the DART trial, of the group randomized to
ingest dietary fish, a subgroup chose to ingest 1.5 g/d of fish oil capsules
rather than to consume fish. The capsule group had a significant reduction
in CHD death and a significant reduction in all-cause mortality, suggesting
that the benefits of the fish consumption were in the fish oil fraction (Burr
et al., 1994). In the Indian Experiment of Infarct Survival, MI survivors
were treated with either fish oil capsules (1.08 g/d of EPA) or mustard oil
(2.9 g/d of Î±-linolenic acid) or placebo for 1 year (Singh et al., 1997). The
fish oil and mustard oil groups had decreased total cardiac events, non-
fatal infarctions, arrhythmias, left ventricular enlargement, and angina

829
M ACRONUTRIENTS AND HEALTHFUL DIETS
pectoris. The fish oil group, but not the mustard oil group, had decreased
cardiac deaths. In the Lyon Diet Heart Study, post-MI patients were
randomized into a control group or into an experimental group that
received dietary counseling and a special margarine containing Î±-linolenic
acid (de Lorgeril et al., 1994, 1999). The control and experimental groups
consumed approximately 0.27 and 0.81 percent of energy as Î±-linolenic
acid, respectively. There was a significant reduction in risk for cardiac
death for the experimental group after 27 months, and a reduction after a
4-year follow-up. The extent to which these reductions in risk were due to
n-3 fatty acids is uncertain.
In another trial, patients with recent MI were randomized to receive
300 mg of vitamin E, 850 mg of n-3 fatty acids (EPA+DHA), both, or neither
(GISSI-Prevenzione Investigators, 1999). After 3.5 years, the n-3 fatty acid
group experienced a 15 percent reduction in the primary endpoints of
death, nonfatal myocardial infarction, and nonfatal stroke, and a 20 per-
cent reduction in the other primary endpoints of cardiovascular death,
nonfatal myocardial infarction, and nonfatal stroke. This group also expe-
rienced a 20 percent reduction in all-cause mortality and a 45 percent
reduction in sudden deaths compared with the control group. Vitamin E,
in contrast to n-3 polyunsaturated fatty acids, had no beneficial effects on
cardiovascular endpoints.
n-3 Polyunsaturated fatty acids have also been reported to reduce
blood pressure in hypertensive individuals. A meta-analysis of 31 placebo-
controlled trials estimated a mean reduction in systolic and diastolic blood
pressure of 3.0 and 1.5 mm Hg, respectively (Morris et al., 1993). Further-
more, a statistically significant doseâresponse effect occurred with the
smallest reduction observed with intakes of less than 3 g/d and the largest
reduction observed with intakes at 15 g/d.
When 55 individuals were randomized to receive either 5.2 g/d of n-3
fatty acids or a placebo for 12 weeks, heart rate variability (naturally occur-
ring irregular heart beats) significantly increased after supplementation
with n-3 fatty acids (Christensen et al., 1997). Because impaired heart rate
variability is associated with increased arrhythmic events (Farrell et al.,
1991), this finding supports the hypothesis that n-3 polyunsaturated fatty
acids have antiarrhythmic effects in humans (Christensen et al., 1997). A
more recent study by Christensen and coworkers (1999) reported a doseâ
response effect on heart rate variability, suggesting antiarrhythmic effects
in men but not women, given 3 g/d of EPA plus 2.9 g/d of DHA or 0.9 g/d
of EPA plus 0.8 g/d of DHA for 12 weeks. However, the beneficial effect
was found only in men with low initial heart rate variability.

832 DIETARY REFERENCE INTAKES
Risk of Obesity
One study in laboratory mice suggested that diets containing n-3 poly-
unsaturated fatty acids lead to lower levels of fat accumulation compared
with diets containing other fatty acids (Hun et al., 1999). Several studies
have examined whether n-3 polyunsaturated fatty acids affect growth of
adipose tissue. Parrish and colleagues (1990, 1991) found that rats given a
high fat diet supplemented with fish oil had less fat in perirenal and
epididymal fat pads and decreased adipocyte volumes compared with rats
fed lard. Adipose tissue growth restriction appeared to be the result of
limiting the amount of triacylglycerol in each adipose tissue cell rather
than by limiting the number of cells. Rustan and colleagues (1993) found
similar results using rats fed either lard or lard supplemented with EPA
and DHA. Although body weight gain and mean energy expenditure were
similar for both groups, the mean respiratory quotient was significantly
higher during both fasting and fed periods in rats fed the EPA+DHA
supplement. The researchers concluded that the rats supplemented with
n-3 fatty acids demonstrated reduced oxidation of fat and increased carbo-
hydrate utilization. Little data exist with respect to the specific effects of
dietary n-3 polyunsaturated fatty acids on adiposity in humans; therefore,
prevention of obesity cannot be considered an indicator at this time.
Risk of Diabetes
Epidemiological Evidence. While several studies have reported a nega-
tive relationship between polyunsaturated fatty acid intake and risk of
diabetes (Colditz et al., 1992; SalmerÃ³n et al., 2001; Trevisan et al., 1990),
fish intake has specifically been reported to have a negative association
(Feskens et al., 1991b, 1995). A review of the epidemiological data on this
association concluded that polyunsaturated fatty acids, and possibly long-
chain n-3 fatty acids, could be beneficial in reducing the risk of diabetes
(Hu et al., 2001).
Interventional Evidence. Studies conducted in rodents have shown that
administration of fish oil results in increased insulin sensitivity (Chicco et
al., 1996) and corrected hyperinsulinemia (Luo et al., 1996). Substituting
a proportion of the fat in a high fat diet with fish oil prevented the devel-
opment of insulin resistance in rats (Storlien et al., 1987) and normalized
insulin action in rats experiencing severe insulin resistance (Storlien et al.,
1991). Additionally, rats prone to spontaneous diabetes mellitus that were
given EPA in doses of 0.1, 0.3, and 1.0 g/kg/d for 8 months had reduced
incidences of diabetes (92, 50, and 17 percent, respectively) (Nobukata et

834 DIETARY REFERENCE INTAKES
associations were reported in the few studies that have examined fish con-
sumption and risk of prostate cancer (Giovannucci et al., 1993; Severson
et al., 1989; Talamini et al., 1992).
Risk of Nutrient Inadequacy
Vegetable oils, such as soybean oil, flaxseed oil, and canola oil, contain
high amounts of Î±-linolenic acid. Fatty fishes and fish oils provide a mix-
ture of biologically active EPA and DHA. n-3 Polyunsaturated fatty acids
(Î±-linolenic acid) are essential in the diet and Adequate Intakes (AIs)
have been set (see Chapter 8). Intakes of Î±-linolenic acid range from
approximately 0.6 to 1.2 percent of energy (Appendix Tables E-1 and E-
11). Low intakes of Î±-linolenic acid can result in inadequate biosynthesis
of the longer-chain n-3 polyunsaturated fatty acids, resulting in an exces-
sive ratio of n-6 polyunsaturated fatty acids (see Chapter 8).
High n-3 Polyunsaturated Fatty Acid Diets
There is evidence to suggest that high intakes of n-3 polyunsaturated
fatty acids (EPA and DHA) may have adverse effects on immune function
and may increase the risk of excessive bleeding and hemorrhagic stroke
(see Chapter 8). High intakes of n-3 polyunsaturated fatty acids (Î±-linolenic
acid) can also result in inadequate biosynthesis of long chain n-6 poly-
unsaturated fatty acids that are important for prostaglandin and eicosanoid
synthesis (see Chapter 8).
Acceptable Macronutrient Distribution Range
Î±-Linolenic acid is essential in the diet and therefore AIs have been
set (see Chapter 8). Up to 10 percent of the AI can be consumed as EPA
and/or DHA. The above studies suggest that Î±-linolenic acid, EPA, and
DHA may provide beneficial health effects when consumed at moderate
levels. Based on the median energy intake by the various age groups
(Appendix Table E-1), it is estimated that approximately 0.6 percent of
energy from Î±-linolenic acid is needed to meet the AI. This level is used as
the lower boundary for the Acceptable Macronutrient Distribution Range
(AMDR) for Î±-linolenic acid. The upper boundary of the AMDR for
Î±-linolenic acid is set at 1.2 percent of energy and represents the highest
levels of Î±-linolenic acid consumed in the form of foods by individuals in
North America. Data from interventional studies to support the benefit of
even higher intakes of Î±-linolenic acid were not considered strong enough
to justify establishing an upper boundary greater than 1.2 percent of

835
M ACRONUTRIENTS AND HEALTHFUL DIETS
energy. Approximately 10 percent of the AMDR for n-3 fatty acids
(Î±-linolenic acid) can be consumed as EPA and/or DHA (0.06 to 0.12 per-
cent of energy).
SATURATED FATTY ACIDS, TRANS FATTY ACIDS,
AND CHOLESTEROL
Low Saturated Fatty Acid, Trans Fatty Acid, and Cholesterol Diets
There are no known risks of chronic disease from consuming low
intakes of saturated fatty acids, trans fatty acids, or cholesterol. In the
United States, saturated fatty acids provided 11 to 12 percent of energy in
adult diets and 12.2 to 13.9 percent of energy in the diets of children and
adolescents (CDC, 1994). It is estimated that the intake of trans fatty acids
is approximately 2.6 percent of energy (Allison et al., 1999). The intake
of cholesterol by American adults ranges from less than 100 mg/d to just
under 770 mg/d (Appendix Table E-15).
It is important to recognize that lower intakes of saturated fatty acids
and cholesterol are observed for vegetarians, especially vegans (Janelle
and Barr, 1995; Shultz and Leklem, 1983). Because certain micronutrients,
saturated fats, and cholesterol are consumed mainly through animal foods,
it is possible that diets low in saturated fat and cholesterol are associated
with low intakes of these micronutrients. When the micronutrient intakes
of Seventh-day Adventist vegetarians and nonvegetarians were measured,
there were no significant reductions in micronutrient intakes with the
lower saturated fat (7.3 versus 12.6 percent of energy) and cholesterol
intakes (186 versus 404 mg/d) of vegetarian compared to nonvegetarian
men (12.6 percent of energy and 404 mg/d) (Shultz and Leklem, 1983).
Similarly, the intakes of most micronutrients were not significantly lower
for vegans, except for vitamin B12 (0.51 versus 3.79 mg/d), riboflavin
(1.32 versus 1.72 mg/d), and calcium (578 versus 950 mg/d). Vegans had
significantly lower intakes of saturated fat (6.9 versus 10.6 percent of energy)
and cholesterol (94 versus 231 mg/d) than nonvegetarians (Janelle and
Barr, 1995).
Analysis of nutritionally adequate menus indicates that there is a mini-
mum amount of saturated fat that can be consumed so that sufficient
levels of linoleic and Î±-linolenic acid are consumed (as an example see
Appendix Tables G-1 and G-2). Other than soy products that are high in
n-6 and n-3 fatty acids, many vegetable-based fat sources are also high in
saturated fatty acids, and these differences should be considered in plan-
ning menus.

836 DIETARY REFERENCE INTAKES
High Saturated Fatty Acid, Trans Fatty Acid, and Cholesterol Diets
There is a body of evidence suggesting that saturated and trans fatty
acids and cholesterol increase blood total and low density lipoprotein
cholesterol concentrations, and therefore the risk of coronary heart dis-
ease (CHD) (see Chapters 8 and 9). Because the intake of each of these
three nutrients and risk of CHD is a positive linear trend, even very low
intakes of each may increase risk.
To minimize saturated fatty acid intake requires decreased intake of
animal fats (e.g., meat fat and butter fat) and certain oils, such as coconut
and palm kernel oil. Saturated fatty acids can be reduced by choosing lean
cuts of meat, trimming away visible fat on meats, and eating smaller por-
tions. The amount of butter that is added to foods can be minimized or
replaced with vegetable oils or nonhydrogenated vegetable oil spreads.
Vegetable oils, such as canola and safflower oil, can be used to replace
more saturated oils such as coconut and palm oil. Such changes can reduce
saturated fat intake without altering the intake of essential nutrients.
A reduction in the frequency of intake or serving size of certain foods
such as liver (375 mg/3 oz slice) and eggs (250 mg/egg) can help reduce
the intake of cholesterol, as well as foods that contain eggs, such as cheese-
cake (170 mg/slice) and custard pie (170 mg/slice). There are a number
of meats and dairy products that contain low amounts of cholesterol (e.g.,
lean meats [30 mg/2 slices] and 2 percent milk [18 mg/cup]). Therefore,
there are a variety of foods that are low in saturated fat and cholesterol
and also abundant in essential nutrients such as iron, zinc, and calcium.
Trans fatty acids are high in stick margarine and those foods containing
vegetable shortenings that have been subjected to hydrogenation. Examples
of foods that contain relatively high levels of trans fatty acids include cakes,
pastries, doughnuts, and french fries (Litin and Sacks, 1993). Therefore,
the intake of trans fatty acids can be reduced without limiting the intake of
most essential nutrients by decreasing the serving size and frequency of
intake of these foods, or by using unhardened oil.
CONJUGATED LINOLEIC ACID
Conjugated linoleic acid (CLA) has been shown to play a role in the
alteration of body composition in animals (Park et al., 1997), the inhibition
of tumor cell growth (Whigham et al., 2000), and the inhibition of experi-
mental atherosclerosis in animals (Lee et al., 1994). The trans-10,cis-12
CLA isomer appears to be the isomer primarily responsible for the induc-
tion of changes in body composition (de Deckere et al., 1999; Park et al.,
1999). Several studies suggest that these changes are primarily due to a
reduction in lipid uptake by adipocytes (Pariza et al., 2001), which results

837
M ACRONUTRIENTS AND HEALTHFUL DIETS
from the action of CLA on the activities of stearoyl-coenzyme A desaturase
(Choi et al., 2000; Lee et al., 1998) and lipoprotein lipase (Park et al.,
1997, 1999). The trans-10,cis-12 CLA isomer has also been reported to
inhibit proliferation and differentiation in cultured mouse adipocytes (Brodie
et al., 1999) and to induce apoptosis in vivo in the adipose tissue of mice
(Tsuboyama-Kasaoka et al., 2000). In addition to body fat reduction, dietary
CLA may increase whole body protein accretion in animals, suggesting the
enhancement of lean body mass (Ostrowska et al., 1999; Park et al., 1997;
Stangl, 2000).
Research on the effects of CLA on body composition in humans has
provided conflicting results. Blankson and coworkers (2000) conducted a
study in overweight and obese men and women given either placebo or
1.7, 3.4, 5.1, or 6.8 g/d of a CLA preparation consisting of equal parts of
the cis-9,trans-11 and trans-10,cis-12 isomers. After 12 weeks, none of the
groups exhibited significant reductions in body weight or body mass index.
However, the groups given 1.7, 3.4, and 6.8 g/d of CLA showed significant
decreases in body fat mass compared to the placebo group. No differences
in lean body mass were observed. Zambell and coworkers (2000) studied
the effects of CLA supplementation in healthy adult women given either
placebo or 3 g/d of CLA for 64 days. They found no significant changes in
fat-free mass, fat mass, body weight, or percentage of body fat with CLA
supplementation.
CLA has been studied for its potential anticancer benefits in numerous
animal and in vitro models. CLA mixtures have been shown to exhibit
anticarcinogenic properties in skin, lung, forestomach, colorectal, prostate,
and mammary tissues (Cesano et al., 1998; Ha et al., 1990; Liew et al.,
1995; SchÃ¸nberg and Krokan, 1995; Shultz et al., 1992), although the
majority of the research has been conducted with breast cancer. Ip and
Scimeca (1997) conducted a study in female rats chemically induced for
mammary tumors and fed a diet containing either 2 percent or 12 percent
linoleic acid. The rats were also supplemented with 0, 0.5, 1, 1.5, or 2 per-
cent CLA. The researchers found that increasing CLA from 0.5 to 1 per-
cent resulted in a dose-dependent decrease in both tumor incidence and
total number of tumors. No further protection was observed in the groups
receiving 1.5 or 2 percent CLA. In addition to inhibiting tumor growth,
CLA eliminated the spread of breast cancer cells to the lungs, peripheral
bone, and bone marrow of mice supplemented with 1 percent CLA
(Visonneau et al., 1997).
Although the exact mechanisms of the anticarcinogenic effects of CLA
are not fully understood, several explanations have been offered. It has
been suggested that growth inhibition of cancer cells may be due to the
ability of CLA to inhibit protein and nucleotide biosynthesis (Ip et al.,
1999; Shultz et al., 1992) and to induce cell apoptosis (Ip et al., 1999,

839
M ACRONUTRIENTS AND HEALTHFUL DIETS
High Fiber Diets
There is limited data to suggest that chronic consumption of high
fiber diets results in adverse health effects (see Chapter 7). Gastrointestinal
distress can occur with the consumption of high fiber diets, but this often
subsides with time.
DIETARY PROTEIN
Low Protein Diets
Although uncommon in North America, proteinâenergy malnutrition
(PEM) is one of the most common nutritional diseases in developing coun-
tries (Torun and Chew, 1999). The etiology of PEM is complex as there
are a number of factors that are attributed to its onset, including insuffi-
cient food intake or intake of low protein-containing foods, which in turn
is attributed to poverty, unsanitary conditions, and food insecurity. Because
PEM is attributed to insufficient food intake, not only are protein and
energy limited, but the micronutrients that are often present in protein-
containing foods are also limited. Epidemiological analysis from 53 devel-
oping countries indicated that 56 percent of deaths in young children
were due to the potentiating effects of malnutrition in infectious diseases
(Pelletier et al., 1995). The increased duration or susceptibility to infec-
tious diseases such as respiratory infections and diarrhea are due, in part,
to the involvement of protein in immune function.
Impaired Immune Function
Chandra (1972) showed that in individuals with PEM, a variety of
immune responses were impaired. The major defects observed with severe
PEM involve T lymphocytes and the complement system. With PEM, the
number of lymphocytes is markedly reduced and delayed cutaneous hyper-
sensitivity responses to both recall and new antigens are depressed
(Chandra, 1991), as is the production of several components of the
complement system (Keusch et al., 1984). Furthermore, antibody affinity
(Chandra et al., 1984) and lysozyme concentrations (Chandra and
Newberne, 1977) are decreased.
Impaired Growth
Low protein intake during pregnancy is correlated with a higher inci-
dence of low birth weight (King, 2000). Furthermore, in children, diets
low in protein and energy are most frequently associated with a deficit in

840 DIETARY REFERENCE INTAKES
weight-for-height (wasting) and height-for-age (stunting) (Waterlow,
1976). These deficits can be corrected by the provision of a high protein
diet (Badaloo et al., 1999) and with an adequate energy intake to permit
catch-up growth. For these reasons, various anthropometric measures are
used for diagnosis and monitoring the treatment of PEM.
Low Birth Weight
Rush and coworkers (1980) found decreases in both gestational length
and birth weight and increases in very early premature births and mortal-
ity with high density protein supplementation (additional 40 g/d) in poor,
black pregnant women at risk of having low birth weight infants. In
contrast, Adams and coworkers (1978) reported no differences from the
controls in mean birth weights of infants of mothers at risk of having a low
birth weight infant when these women were supplemented with 40 g/d of
protein. No reports were found of protein toxicity in healthy pregnant or
lactating women that were not at risk of having a low birth weight infant.
Thus, at the present time, low birth weight cannot be utilized to set a
Tolerable Upper Intake Level (UL) for protein for women.
Risk of Nutritional Inadequacy
High quality protein is typically consumed via animal products, and
therefore vegetarians may consume less high quality protein than omni-
vores. Because animal foods are the primary sources of certain nutrients,
such as calcium, vitamin B12, and bioavailable iron and zinc, low protein
intakes may result in inadequate intakes of these micronutrients. As an
example, Janelle and Barr (1995) reported significantly lower intakes of
riboflavin, vitamin B12, and calcium by vegans who also consumed lower
amounts of protein (10 versus 15 percent of energy) compared with
nonvegetarians.
Vegetable protein has been shown to decrease plasma cholesterol con-
centrations in experimental animals and humans (Nagata et al., 1998;
Nicolosi and Wilson, 1997; Terpstra et al., 1991). When the ratio of
casein:soybean protein in the diet was decreased, there was a reduction in
total and non-high density lipoprotein cholesterol concentrations (Fernandez
et al., 1999; Teixeira et al., 2000). In laboratory animals, it was shown that
the onset of atherosclerosis was significantly reduced when animals were
fed a textured vegetable protein diet compared to a beef protein diet
(Kritchevsky et al., 1981).

841
M ACRONUTRIENTS AND HEALTHFUL DIETS
High Protein Diets
Osteoporosis
There is a substantial amount of literature that documents the increase
in urinary excretion of calcium with increasing protein intake (Allen et al.,
1979; Heaney, 1993; Lemann, 1999). The magnitude of this effect for a
doubling of the protein intake, in the absence of change in any other
nutrient, is a 50 percent increase in urinary calcium (Heaney, 1993). This
has two potential detrimental consequences: loss of bone calcium and
increased risk of renal calcium stone formation. Loss of calcium from
bone is thought to occur because of bone mineral resorption that provides
the buffer for the acid produced by the oxidation of the sulfur amino
acids of protein (Barzel and Massey, 1998). However, although increased
resorption of bone with increased protein intake has been shown
(Kerstetter et al., 1999; Whiting et al., 1997), whether this in practice leads
to bone loss and osteoporosis is controversial (Barzel and Massey, 1998;
Heaney, 1998). It has recently been concluded that there may be no need
to restrain dietary protein intake. Poor protein status itself leads to bone
loss, whereas increased protein intake may lead to increased calcium intake,
and bone loss does not occur if calcium intake is adequate (Heaney, 1998).
In a recent prospective study of men and women aged 55 to 92 years,
consumption of animal protein was positively associated with bone mineral
density in women, but not in men (Promislow et al., 2002). In contrast,
Dawson-Hughes and Harris (2002) reported no association between
protein intake and bone mineral density in 342 healthy men and women
aged 65 years and older. However, when the individuals were given cal-
cium citrate malate and vitamin D in addition to the high protein intake,
there was a favorable change in bone mineral density.
Kidney Stones
It has been estimated that 12 percent of the population in the United
States will suffer from a kidney stone at some time (Sierakowski et al.,
1978). The most common form of kidney stone is composed of calcium
oxalate, and its formation is promoted by high concentrations of calcium
and oxalate in the urine. A high animal protein intake in healthy humans
increases urinary calcium and oxalate and the overall probability of form-
ing kidney stones by 250 percent (Robertson et al., 1979). Conversely,
restricting protein intake improved the lithogenic profile in hypercalciuric
patients (Giannini et al., 1999). Also, the incidence of calcium oxalate
stones has been shown to be associated with consumption of animal pro-
tein (Curhan et al., 1996; Robertson and Peacock, 1982). In contrast, the

842 DIETARY REFERENCE INTAKES
only long-term prospective trial (4.5 years) of the effect of animal protein
restriction on stone formation in newly diagnosed patients with calcium
stones gave a negative result (Hiatt et al., 1996). The relative risk factor for
recurrent stone formation was 5.6 (confidence interval 1.2â26.1), suggest-
ing that the dietary advice was detrimental. In this study, 50 patients were
given low animal protein (56 to 64 g/d) and high fiber, plus adequate
fluid and calcium, whereas 49 control patients were only instructed to take
adequate water and calcium. However, as protein intake was not the only
variable, and in view of the data described above suggesting benefits from
lower protein intake, further investigation is necessary.
Renal Failure
Restriction of dietary protein intake is known to lessen the symptoms
of chronic renal insufficiency (Walser, 1992). This raises two related, but
distinct questions: Do high protein diets have some role in the develop-
ment of chronic renal failure? Do high protein intakes accelerate the pro-
gression of chronic renal failure? The concept that protein restriction
might delay the deterioration of the kidney with age was based on studies
in rats in which low energy or low protein diets attenuated the develop-
ment of chronic renal failure (Anderson and Brenner, 1986, 1987). Walser
(1992) has argued that this mechanism is unlikely to operate in humans.
In particular, the decline in kidney function in the rat is mostly due to
glomerulosclerosis, whereas in humans it is due mostly to a decline in
filtration by nonsclerotic nephrons. Also, when creatinine clearance was
measured in men at 10- to 18-year intervals, the decline with age did not
correlate with dietary protein intake (Tobin and Spector, 1986). Correla-
tion of creatinine clearance with protein intake showed a linear relation-
ship with a positive gradient (Lew and Bosch, 1991), suggesting that the
low protein intake itself decreased renal function. These factors point to
the conclusion that the protein content of the diet is not responsible for
the progressive decline in kidney function with age.
Coronary Artery Disease
It is well documented that high dietary protein in rabbits induces
hypercholesterolemia and arteriosclerosis (Czarnecki and Kritchevsky,
1993). However, this effect has not been consistently shown in either swine
(Luhman and Beitz, 1993; Pfeuffer et al., 1988) or humans. In humans,
analysis of data from the Nursesâ Health Study showed an inverse relation-
ship between protein intake and risk of cardiovascular disease (Hu et al.,
1999). The association was weak but suggests that high protein intake does
not increase the risk of cardiovascular disease. Similar conclusions have

844 DIETARY REFERENCE INTAKES
ship with total protein intake, but there was an increased risk ratio for
meat consumption (Toniolo et al., 1994).
For other types of tumors, there also is no clear indication of greater
risk with higher protein intakes. Total protein intake was not associated
with increased risk of lung cancer (Lei et al., 1996), prostate cancer
(Schuurman et al., 1999), endometrial cancer (Barbone et al., 1993; Shu
et al., 1993), oral and pharynx cancer (Franceschi et al., 1999), esophogeal
cancer (Gao et al., 1994), and non-Hodgkinâs lymphoma (Chiu et al., 1996;
Ward et al., 1994), although some studies detected a positive relationship
with animal protein (Chiu et al., 1996; Shu et al., 1993) or cured meat
consumption (Schuurman et al., 1999). Moreover, in some of these studies,
there was an inverse relationship with total protein intake (Barbone et al.,
1993; Franceschi et al., 1999; Gao et al., 1994). On the other hand, higher
protein intake was associated with an increased risk of cancer of the upper
digestive tract (De Stefani et al., 1999) and kidney (Chow et al., 1994).
Overall, despite the demonstration of a positive influence of dietary
fat and total energy, as well as meat (especially red meat), on some types of
tumors, no clear role for total protein has yet emerged. The current state
of the literature, therefore, does not permit any recommendation of an
upper limit to be made on the basis of cancer risk.
Acceptable Macronutrient Distribution Range
There is no evidence to suggest that the Acceptable Macronutrient
Distribution Range (AMDR) for protein should be at levels below the Rec-
ommended Dietary Allowance (RDA) for protein (about 10 percent of
energy) for adults. There was insufficient evidence to suggest a UL for
protein (see Chapter 10) and insufficient data to suggest an upper limit
for an AMDR for protein. To complement the AMDRs for fat (20 to 35 per-
cent energy) and carbohydrate (45 to 65 percent energy) for adults, pro-
tein intakes may range from 10 to 35 percent of energy intake to ensure a
nutritionally adequate diet. For young and older children, the RDA is
approximately 5 and 10 percent of energy, respectively. To complement
the AMDR for fat (30 to 40 percent of energy) and carbohydrate (45 to
65 percent of energy) for young children and for older children (25 to
35 percent of energy from fat and 45 to 65 percent of energy from carbo-
hydrate), protein intakes may range from 5 to 20 percent for young chil-
dren and 10 to 30 percent for older children.

Responding to the expansion of scientific knowledge about the roles of nutrients in human health, the Institute of Medicine has developed a new approach to establish Recommended Dietary Allowances (RDAs) and other nutrient reference values. The new title for these values Dietary Reference Intakes (DRIs), is the inclusive name being given to this new approach. These are quantitative estimates of nutrient intakes applicable to healthy individuals in the United States and Canada. This new book is part of a series of books presenting dietary reference values for the intakes of nutrients. It establishes recommendations for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids. This book presents new approaches and findings which include the following:

The establishment of Estimated Energy Requirements at four levels of energy expenditure

Recommendations for levels of physical activity to decrease risk of chronic disease

The establishment of RDAs for dietary carbohydrate and protein

The development of the definitions of Dietary Fiber, Functional Fiber, and Total Fiber

The establishment of Adequate Intakes (AI) for Total Fiber

The establishment of AIs for linolenic and a-linolenic acids

Acceptable Macronutrient Distribution Ranges as a percent of energy intake for fat, carbohydrate, linolenic and a-linolenic acids, and protein

Research recommendations for information needed to advance understanding of macronutrient requirements and the adverse effects associated with intake of higher amounts

Also detailed are recommendations for both physical activity and energy expenditure to maintain health and decrease the risk of disease.

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